Ring-fused compound

ABSTRACT

The present invention relates to a compound that has URAT1 inhibitory action, and a URAT1 inhibitor, a blood uric acid level-reducing agent and a pharmaceutical composition comprising the compound. More specifically, the present invention relates to a compound represented by Formula (I) below. 
                         
[in the formula,
         R 1  is -Q 1 -A 1  and the like;   is a double bond or a single bond; when   is a double bond, W 1  is a nitrogen atom or a group represented by the general formula: ═C(R a )—, and W 2  is a nitrogen atom or a group represented by the general formula: ═C(R b )—; when   is a single bond, W 1  is a group represented by the general formula: —C(R aa )(R ab )— or a group represented by the general formula: —(C═O)—, and W 2  is a group represented by the general formula: —C(R ba )(R bb )—, a group represented by the general formula: —(C═O)— or a group represented by the general formula: —N(R bc )—; W 3 , W 4  and W 5  are each independently a nitrogen atom or a methine group and the like that may have a substituent; X is a single bond, an oxygen atom and the like; Y is a single bond or (CR Yi R Yi′ ) n ; and Z is a hydroxyl group or COOR 2  and the like.

This is a Rule 53(b) Divisional of application Ser. No. 13/982,200 filedJul. 26, 2013, which is a National Stage of International ApplicationNo. PCT/JP2012/052009 filed Jan. 30, 2012, claiming priority based onJapanese Patent Application NO. 2011-016950 filed Jan. 28, 2011, thecontents of all of which are incorporated herein by reference in theirentirety.

TECHNICAL FIELD

The present invention relates to a ring-fused compound that is useful inthe field of a medicine. Further specifically, the present inventionrelates to a ring-fused compound that has URAT1 inhibitory activity andis useful in the field of treatment of diseases associated with blooduric acid, and an URAT1 inhibitor, a blood uric acid level-reducingagent and a pharmaceutical composition containing the compound.

BACKGROUND ART

Uric acid is a final product of a purine metabolism in humans. Thepurine nucleotide is generated by degradation of a nucleic acid in thecell, ATP that is an energy source in a living body, and the like, or isabsorbed from a meal. The purine nucleotide is metabolized to uric acidvia hypoxanthine and xanthine. Uric acid is a final product of thepurine metabolism in the higher primates including human as urateoxidase (uricase) is genetically silenced in these species. In manyother mammals, uric acid is oxidized by uricase, and metabolized toallantoin.

About 98% of uric acid is present in the form of sodium urate in a bodyliquid (Non Patent Literature 1).

Since the solubility of sodium urate at physiological pH conditions is6.4 mg/dL (Non Patent Literature 1), 7 mg/dL or more of the blood uricacid level beyond the solubility in the body liquid is defined ashyperuricemia (Non Patent Literature 2).

If the hyperuricemia persists, urate is crystallized and precipitated inthe body liquid, which cause gout arthritis, gouty kidney, gouty node,urolithiasis, a renal function disorder and the like (Non PatentLiterature 3).

In addition, in recent years, the hyperuricemia is known to becomplicated with lifestyle diseases such as hypertension,hyperlipidaemia, impaired glucose tolerance and obesity in high rate(Non Patent Literatures 4, 5, 6 and 7), and such complications are knownto increase the incidence rate of cardiovascular or cerebrovasculardisorders.

The hyperuricemia is reported to be present in 20% or more of adultmales in Japan, and tends to increase even now due to westernizedlifestyle and the like (Non Patent Literature 8). As for theclassification of hyperuricemia, the overproduction of uric acid isreported to be 12%, the decreased uric acid excretion to be 60% and thecombined type to be 25% (Non Patent Literature 9). Thus, the decreaseduric acid excretion is seen in 85% that is the sum of 60% of thedecreased uric acid excretion and 25% of the combined type, whichsuggests the importance of the decreased uric acid excretion withrespect to the cause of hyperuricemia.

Uric acid is mainly excreted from a kidney. In humans, about 70% isexcreted from the kidney, and 30% is excreted from extra-renal pathwaysuch as a bile or a saliva, a sweat and the like. The uric acid isfiltered by 100% in a renal glomerulus, and then most part of it isre-absorbed in a proximal tubule, and about 10% is excreted in aterminal urine (Non Patent Literatures 3 and 10). Thus, it is suggestedthat uric acid excretion is strictly regulated by the re-absorption.

Since uric acid is present as an organic acid at physiological pHconditions, it was expected that a transporter responsible forre-absorption of uric acid has similar structural characteristics withan organic anion transporter family proteins. In recent years, URAT1 wasidentified as a transporter responsible for re-absorption of uric acid,which is present in the proximal tubule (Non Patent Literature 11).URAT1 is a 12-transmembrane transporter belonging to the SLC family.Northern blotting analysis showed that an expression of a URAT1 gene islocalized in the kidney of an adult and fetus. It became clear fromimmunohistochemical analysis using anti-human URAT1 antibody that anURAT1 protein is present on a luminal surface of the proximal tubule.Furthermore, since uric acid is incorporated when URAT1 is expressed ina xenopus oocyte, it was confirmed that URAT1 can transport of uric acid(Non Patent Literature 11).

Further, it became clear that loss of function caused by mutations ofthe URAT1 gene leads to renal hypouricemia, and thus importance of URAT1with respect to uric acid excretion came to the fore (Non PatentLiteratures 11 and 12).

Currently used uricosuric agents, benzbromarone and probenecid have beenshown to inhibit uric acid-transport activity of URAT1, and importancein the uric acid excretion of URAT1 has been cleared pharmacologicallyas well (Non Patent Literature 13).

From these, it is regarded that a drug inhibiting URAT1 can reduce theblood uric acid level by suppressing re-absorption of uric acid in theproximal tubule and by accelerating the uric acid excretion, and thedrug inhibiting URAT1 is useful as an agent for treating or preventingpathological conditions associated with uric acid, specifically,hyperuricemia, gouty node, gout arthritis, gouty kidney, urolithiasisand renal function disorders. In addition, the drug inhibiting URAT1 isalso useful as an agent for treating or preventing hypertension,hyperlipidaemia, abnormal glucose tolerance, obesity, a coronary arterydiseases and cerebrovascular disorders, which are associated withhyperuricemia.

Incidentally, as a compound that has URAT1 inhibitory action, forexample, Patent Literature 1 discloses a compound of the general formuladescribed below.

Patent Literature 2 discloses a compound of the general formuladescribed below.

Patent Literature 3 discloses a compound of the general formuladescribed below.

Patent Literature 4 discloses a compound of the general formuladescribed below as a PDE5 (phosphodiesterase 5) inhibitor.

Patent Literature 5 discloses a compound of the general formuladescribed below as a PDE5 inhibitor.R¹—SO₂NHCO-A-R²

Patent Literature 6 discloses a compound of the general formuladescribed below as a 17β HSD (17β-hydroxysteroid dehydrogenase) type 5inhibitor.

CITATION LIST Patent Literatures

-   Patent Literature 1: WO 2006/057460 A-   Patent Literature 2: WO 2007/086504 A-   Patent Literature 3: WO 2009/151695 A-   Patent Literature 4: WO 98/15530 A-   Patent Literature 5: WO 99/00372 A-   Patent Literature 6: WO 2007/100066 A

Non Patent Literatures

-   Non Patent Literature 1: Loeb J N., Arthritis Rhueum., 15, 189-192,    1972-   Non Patent Literature 2: Japanese Society of Gout and Nucleic Acid    Metabolism, the 2^(nd) Edition of Guideline of Hyperuricemia or Gout    Treatment, 30-31, 2010-   Non Patent Literature 3: Choi H K. et al. Ann. Intern. Med.,    43,499-516, 2005-   Non Patent Literature 4: Taniguchi Y. et al., J. Hypertension, 19,    1209-1215, 2001-   Non Patent Literature 5: Sunderstrom J. et al., Hypertension, 45,    28-33, 2005-   Non Patent Literature 6: Choi H K. et al., The Am. J. Med., 120,    442-447, 2007-   Non Patent Literature 7: Ishizaka N. et al., Arterioscler. Thromb.    Vasc. Biol., 25, 1038-1044, 2005-   Non Patent Literature 8: TOMITA Masako, MIZUNO Shouichi, Gout and    Nucleic Acid Metabolism, 30, 1-5, 2006-   Non Patent Literature 9: NAKAMURA Toru, Treatment of Hyperuricemia    and Gout, Medical Review Co., Ltd., 21-39, 2003-   Non Patent Literature 10: Sica D A. and Schoolwerth A C., The    Kidney, Saubder, Philadelphia Pa., 680-700, 1996-   Non Patent Literature 11: Enomoto A. et al., Nature, 417, 447-452,    2002-   Non Patent Literature 12: Ichida K. et al., J. Am. Soc. Nephrol. 15,    164-173, 2004-   Non Patent Literature 13: OHNO Iwao, Japan Clinics, 66, 743-747,    2008

SUMMARY OF INVENTION Technical Problem

The above-mentioned benzbromarone or probenecid was shown to inhibit auric acid-transport activity of URAT1, but the URAT1 inhibitory actionthereof was not sufficient. Furthermore, benzbromarone is known to leadto serious hepatic disorders and probenecid is known to lead togastrointestinal tract disorders, and the like. In addition, both of thecompounds are also known to cause drug interaction with other drugs.Therefore, a uric acid excretion facilitator that is safer and highlyeffective, is demanded.

Accordingly, it became problems to provide a novel compound that hasexcellent URAT1 inhibitory action, and an agent for treating orpreventing a disease associated with blood uric acid.

Solution to Problem

The present inventors performed widely synthesis and investigation ofnovel ring-fused compounds to solve the problems, and as a result, foundthat a compound represented by General Formula (I) has excellent URAT1inhibitory action, and completed the present invention.

Specifically, the present invention relates to a compound represented byFormula (I):

[in the formula,

R¹ represents a lower alkyl group that may be substituted with acycloalkyl group, a cycloalkyl group, a halo-lower alkyl group, ahydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a loweralkoxy-carbonyl group, a lower alkyl-sulfonyl group or a grouprepresented by the general formula: -Q¹-A¹;

Q¹ represents a single bond or a lower alkylene group (herein 1 or 2, ormore methylene groups constituting the lower alkylene group eachindependently may be substituted with a carbonyl group, a sulfinyl groupor a sulfonyl group for the total methylene groups, and/or the hydrogenconstituting the methylene group may be substituted with a lower alkylgroup.);

A¹ represents an aryl group or a heteroaryl group, which may besubstituted with one to three substituents selected from the<Substituent group L> described later (herein any two substituentsadjacent to each other on the aryl group or the heteroaryl group mayjoin together to form a lower alkylenedioxy group.);

represents a double bond or a single bond;

when

is a double bond,

W¹ represents a nitrogen atom or a group represented by the generalformula: ═C(R^(a))—, and

W² represents a nitrogen atom or a group represented by the generalformula: ═C(R^(b))—;

when

is a single bond,

W¹ represents a group represented by the general formula:—C(R^(aa))(R^(ab))— or a group represented by the general formula:—(C═O)—, and

W² represents a group represented by the general formula:—C(R^(ba))(R^(bb))—, a group represented by the general formula: —(C═O)—or a group represented by the general formula: —N(R^(bc))—;

R^(a) and R^(b) represent each independently a hydrogen atom, asubstituent selected from the <Substituent group M> described later or agroup represented by the general formula: -Q²-A²;

R^(aa) and R^(ab) represent each independently a hydrogen atom, asubstituent selected from the <Substituent group N> described later or agroup represented by the general formula: -Q²-A², or R^(aa) and R^(ab)may join together to form a lower alkylene group (herein 1 to 2 or moremethylene groups constituting the lower alkylene group eachindependently may be substituted with an oxygen atom, a carbonyl group,a vinylene group or a group represented by the general formula:—N(R^(c))— for the total methylene groups, and/or the hydrogenconstituting the methylene group may be substituted with a hydroxylgroup, a lower alkyl group or a halogen atom.);

R^(ba) and R^(bb) represent each independently a hydrogen atom, ahalogen atom, an amino group, a lower alkyl-amino group, a di-loweralkyl-amino group, a hydroxy-lower alkyl-amino group, a loweralkyl-sulfonylamino group, a lower alkoxy-carbonylamino group, asubstituent selected from the <Substituent group N> or a grouprepresented by the general formula: -Q²-A², or R^(ba) and R^(bb) mayjoin together to form a lower alkylene group (herein 1 to 2 or moremethylene groups constituting the lower alkylene group eachindependently may be substituted with an oxygen atom, a carbonyl group,a vinylene group or a group represented by the general formula:—N(R^(c))— for the total methylene groups, and/or the hydrogenconstituting the methylene group may be substituted with a hydroxylgroup, a lower alkyl group or a halogen atom.);

R^(bc) represents a group selected from the group consisting of ahydrogen atom, a lower alkyl group, a cycloalkyl group, a halo-loweralkyl group, a lower alkoxy-carbonyl group, a carbamoyl group, amono-lower alkyl-carbamoyl group, a di-lower alkyl-carbamoyl group and alower alkanoyl group, or a group represented by the general formula:-Q²-A²;

Q² represents a single bond, a lower alkylene group or a loweralkenylene group (herein 1 or 2, or more methylene groups constitutingthe lower alkylene group each independently may be substituted with anoxygen atom, a nitrogen atom or a carbonyl group for the total methylenegroups, and/or the hydrogen constituting the methylene group may besubstituted with a halogen atom, a cyano group, a hydroxyl group or alower alkyl group.);

A² represents a cycloalkyl group, an aliphatic heterocyclic group, anaryl group or a heteroaryl group, which may be substituted with one tothree substituents selected from the <Substituent group L> (herein anytwo substituents adjacent to each other on the aryl group or theheteroaryl group may join together to form a lower alkylenedioxygroup.);

W³, W⁴ and W⁵ represent each independently a nitrogen atom, or a methinegroup that may have a substituent selected from the group consisting ofa halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, acycloalkyl group, a halo-lower alkyl group, a lower alkoxy group and ahalo lower alkoxy group; provided that zero to four of W¹, W², W³, W⁴and W⁵ are nitrogen atoms;

X represents a single bond, an oxygen atom, a sulfur atom, a sulfinylgroup, a sulfonyl group, a carbonyl group, a lower alkenylene group, alower alkynylene group or a group represented by the general formula:—N(R^(X))— (herein R^(X) is a hydrogen atom or a lower alkyl group.);

Y is a single bond or (CR^(Yi)R^(Yi′))_(n) (herein n is any integer of 1to 6, i is any integer of 1 to n, and (CR^(Yi)R^(Yi′))_(n) represents(CR^(Y1)R^(Y1′)) when n=1; represents (CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))when n=2; represents (CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))—(CR^(Y3)R^(Y3′))when n=3; represents(CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))—(CR^(Y3)R^(Y3′))—(CR^(Y4)R^(Y4′)) whenn=4; represents(CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))—(CR^(Y3)R^(Y3′))—(CR^(Y4)R^(Y4′))—(CR^(Y5)R^(Y5′))when n=5; and represents(CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))—(CR^(Y3)R^(Y3′))—(CR^(Y4)R^(Y4′))—(CR^(Y5)R^(Y5′))—(CR^(Y6)R^(Y6′))when n=6 (herein R^(Y1), R^(Y1′), R^(Y2), R^(Y2′), R^(Y3), R^(Y3′),R^(Y4), R^(Y4′), R^(Y5), R^(Y5′), R^(Y6) and R^(Y6′) are eachindependently a hydrogen atom, a halogen atom or a substituent selectedfrom the <Substituent group N>,

or in relation to R^(X), R^(Y1), R^(Y1′), R^(Y2), R^(Y2′), R^(Y3),R^(Y3′), R^(Y4), R^(Y4′), R^(Y5), R^(Y5′), R^(Y6) and R^(Y6′), thecombinations of the two groups below: “R^(Y1) and R^(Y1′)”, “R^(Y2) andR^(Y2′)”, “R^(Y3) and R^(Y3′)”, “R^(Y4) and R^(Y4′)”, “R^(Y5) andR^(Y5′)”, “R^(Y6) and R^(Y6′)”, “R^(X) and R^(Y1)”, “R^(X) and R^(Y2)”,“R^(X) and R^(Y3)”, “R^(Y1) and R^(Y2)”, “R^(Y1) and R^(Y3)”, “R^(Y1)and R^(Y4)”, “R^(Y2) and R^(Y3)”, “R^(Y2) and R^(Y4)” or “R^(Y2) andR^(Y5)”, i.e., the two groups constituting the combinations may jointogether to form a lower alkylene group, wherein 1 or 2, or moremethylene groups constituting the lower alkylene group eachindependently may be substituted with an oxygen atom, a carbonyl group,a vinylene group or the general formula: —N(R^(c))— for the totalmethylene groups, and/or the hydrogen constituting the methylene groupmay be substituted with a hydroxyl group, a lower alkyl group or ahalogen atom.);

R^(c) represents a hydrogen atom, a lower alkyl group, a halo-loweralkyl group or a lower alkanoyl group;

Z represents a hydroxyl group, COOR², CONR³R⁴, SO₃R², SO₃NR³R⁴, a5-tetrazolyl group, a 5-oxo-1,2,4-oxadiazolyl group, a2-oxo-1,3,4-oxadiazolyl group, a 5-imino-4,5-dihydro-1,3,4-oxadiazolylgroup, a 2-thioxo-1,3,4-oxadiazolyl group or a 5-oxo-1,2,4-thiadiazolylgroup;

wherein R², R³ and R⁴ represent each independently a hydrogen atom or alower alkyl group; and the <Substituent group L>, the <Substituent groupM> and the <Substituent group N> are defined as described below.

<Substituent Group L>:

a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formylgroup, an amino group, a carboxyl group, a lower alkyl group, andhalo-lower alkyl group, a cycloalkyl group, a lower alkoxy group, ahalo-lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxylower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group,a lower alkylthio group and lower alkylsulfonyl group, a loweralkylamino group, a di-lower alkylamino group, a carbamoyl group, amono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, alower alkanoylamino group, a lower alkylsulfonylamino group, a loweralkoxycarbonylamino group, an aralkyl group, an aryloxy group, aheteroaryloxy group, and a lower alkenyl group

<Substituent Group M>:

a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formylgroup, an amino group, a carboxyl group, lower alkyl group, andhalo-lower alkyl group, a cycloalkyl group, a lower alkoxy group, ahalo-lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxylower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group,a lower alkylthio group, lower alkylsulfonyl group, a lower alkylaminogroup, a di-lower alkylamino group, a carbamoyl group, a mono-loweralkyl carbamoyl group, a di-lower alkyl carbamoyl group, a loweralkanoylamino group, a lower alkylsulfonylamino group, and a loweralkoxycarbonylamino group

<Substituent Group N>:

a hydroxyl group, a cyano group, a formyl group, a carboxyl group, alower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a loweralkoxy group, a halo-lower alkoxy group, a hydroxy lower alkyl group, alower alkoxy lower alkyl group, a lower alkoxycarbonyl group, a loweralkanoyl group, a carbamoyl group, a mono-lower alkyl carbamoyl group,and a di-lower alkyl carbamoyl group

or a pharmaceutically acceptable salt and ester of the compound.

Meanwhile, the compound represented by Formula (I) includes not only aracemic mixture of the compound, but also all enantiomers anddiastereomers that is possibly present.

In addition, the present invention relates to a method of treating orpreventing pathological conditions associated with the blood uric acidselected from the group consisting of hyperuricemia, gouty node, acutegout arthritis, chronic gout arthritis, gouty kidney, urolithiasis, arenal function disorder, a coronary artery disease and an ischemic heartdisease in mammals (particularly, humans), which is characterized byadministering a therapeutically effective dose of the compound ofFormula (I) to the mammals.

Further, the present invention relates to a method of treating orpreventing pathological conditions associated with the blood uric acidselected from the group consisting of hyperuricemia, gouty node, acutegout arthritis, chronic gout arthritis, gouty kidney, urolithiasis, arenal function disorder, a coronary artery disease and an ischemic heartdisease in mammals (particularly, humans), which is characterized byadministering a therapeutically effective dose of a URAT1 inhibitor, ablood uric acid level-reducing agent or a pharmaceutical compositioncontaining the compound of Formula (I) to the mammals.

The present invention relates to a URAT1 inhibitor containing thecompound of Formula (I) as an active ingredient.

Further, the present invention relates to a blood uric acidlevel-reducing agent containing the compound of Formula (I) as an activeingredient.

Further, the present invention relates to a treatment agent for treatingor a pharmaceutical composition for preventing pathological conditionsassociated with the blood uric acid selected from the group consistingof hyperuricemia, gouty node, acute gout arthritis, chronic goutarthritis, gouty kidney, urolithiasis, a renal function disorder, acoronary artery disease and an ischemic heart disease, which ischaracterized by containing the compound of (I) as an active ingredient.

Effect of Invention

A compound represented by Formula (I) of the present invention and apharmaceutically acceptable salt and ester of the compound haveexcellent URAT1 inhibitory action as shown in Examples described below,and thus promote uric acid excretion. Accordingly, the compoundrepresented by Formula (I) of the present invention and apharmaceutically acceptable salt and ester of the compound can reducethe blood uric acid level, and are useful as an agent for treating orpreventing pathological conditions associated with the blood uric acidsuch as hyperuricemia, gouty node, acute gout arthritis, chronic goutarthritis, gouty kidney, urolithiasis, a renal function disorder, acoronary artery disease or an ischemic heart disease.

DESCRIPTION OF EMBODIMENTS

Hereinafter, meanings of the terms used in the present invention will bedescribed, and the present invention will be further described indetail.

Examples of the “halogen atom” in Formula (I) include a fluorine atom, achlorine atom, a bromine atom, an iodine atom, and the like.

The “lower alkyl group” in Formula (I) means a C₁₋₆ straight or branchedalkyl group, and examples thereof include a methyl group, an ethylgroup, a propyl group, an isopropyl group, a butyl group, an isobutylgroup, a sec-butyl group, a tert-butyl group, a pentyl group, anisopentyl group, an isoamyl group, a neopentyl group, a1,1-dimethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group,a 1,2-dimethylpropyl group, a hexyl group, an isohexyl group, a1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutylgroup, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a3,3-dimethylbutyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a1,2,2-trimethylpropyl group, a 1-ethyl-3-methylpropyl group and thelike.

The “cycloalkyl group” in Formula (I) means a 3-membered to 8-memberedaliphatic cyclic group and examples thereof include a cyclopropyl group,a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, acycloheptyl group, a cyclooctyl group and the like.

The “halo-lower alkyl group” in Formula (I) means the “lower alkylgroup” in which any substitutable position is substituted with 1 or 2,or more, preferably 1 to 3 of the halogen atoms that are identical ordifferent, and examples thereof include a fluoromethyl group, adifluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a1,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a chloromethylgroup, a 2-chloroethyl group, a 1,2-dichloroethyl group, a bromomethylgroup, an iodomethyl group and the like.

The “lower alkoxy group” in Formula (I) means a group in which ahydrogen atom of a hydroxyl group is substituted with the “lower alkylgroup”, and examples thereof include a methoxy group, an ethoxy group, apropoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group,a tert-butoxy group, a pentyloxy group, an isopentyloxy group, ahexyloxy group, an isohexyloxy group and the like.

The “halo lower alkoxy group” in Formula (I) means the “lower alkoxygroup” in which any substitutable position is substituted with 1 or 2,or more, preferably 1 to 3 of the halogen atoms that are identical ordifferent, and examples thereof include a fluoromethoxy group, adifluoromethoxy group, a trifluoromethoxy group, a 2-fluoroethoxy group,a 1,2-difluoroethoxy group, a 2,2,2-trifluoroethoxy group, achloromethoxy group, a 2-chloroethoxy group, a 1,2-dichloroethoxy group,a bromomethoxy group, an iodomethoxy group and the like.

The “hydroxy-lower alkyl group” in Formula (I) means the “lower alkylgroup” in which any substitutable position is substituted with 1 or 2,or more, preferably 1 or 2 hydroxyl groups, and examples thereof includea hydroxymethyl group, a 1-hydroxyethyl group, a 1-hydroxypropyl group,a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 2-hydroxy-1-methylethyl group, a 1-hydroxy-1-methyl ethyl group, a 1,2-dihydroxyethylgroup, a 3-hydroxypropyl group and the like.

The “lower alkoxy-lower alkyl group” in Formula (I) means the “loweralkyl group” in which any substitutable position is substituted with 1or 2, or more, preferably 1 or 2 of the “lower alkoxy groups” that areidentical or different, and examples thereof include a methoxymethylgroup, an ethoxymethyl group, a 2-methoxyethyl group, a 2-ethoxyethylgroup, a 1-methoxy-1-methylethyl group, a 1,2-dimethoxyethyl group, a3-methoxypropyl group and the like.

The “lower alkoxy-carbonyl group” in Formula (I) means a group in whichthe “lower alkoxy group” and the carbonyl group are bonded to eachother, and is specifically, a C₂₋₇ alkoxycarbonyl group, and examplesthereof include a methoxycarbonyl group, an ethoxycarbonyl group, apropoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonylgroup, an isobutoxycarbonyl group, a tert-butoxycarbonyl group, apentyloxycarbonyl group and the like.

The “lower alkanoyl group” in Formula (I) means a group in which thelower alkyl group and the carbonyl group are bonded to each other, andis specifically a C₂₋₇ alkanoyl group, and examples thereof include anacetyl group, a propionyl group, a butyryl group, an isobutyryl group, avaleryl group, an isovaleryl group, a pivaloyl group and the like.

The “lower alkylthio group” in Formula (I) means a group in which the“lower alkyl group” and a sulfur atom are bonded to each other, and isspecifically a C₁₋₆ alkylthio group, and examples thereof include amethylthio group, an ethylthio group, a propylthio group, anisopropylthio group, a butylthio group, a sec-butylthio group, anisobutylthio group, a tert-butylthio group, a pentylthio group, anisopentylthio group, a hexylthio group, an isohexylthio group and thelike.

The “lower alkyl-sulfonyl group” in Formula (I) means a group in whichthe “lower alkyl group” and a sulfonyl group are bonded to each other,and examples thereof include a methylsulfonyl group, an ethylsulfonylgroup, a propylsulfonyl group, an isopropylsulfonyl group, abutylsulfonyl group, a sec-butylsulfonyl group, an isobutylsulfonylgroup, a tert-butylsulfonyl group, a pentylsulfonyl group, anisopentylsulfonyl group, a hexylsulfonyl group, an isohexylsulfonylgroup and the like.

The “lower alkyl-amino group” in Formula (I) means an N-mono-substitutedamino group with the “lower alkyl group”, and examples thereof includean N-methylamino group, an N-ethylamino group, an N-propylamino group,an N-isopropylamino group, an N-butylamino group, an N-sec-butylaminogroup, an N-tert-butylamino group and the like.

The “di-lower alkyl-amino group” in Formula (I) means aN,N-disubstituted amino group with the “lower alkyl groups” that areidentical or different, and examples thereof include anN,N-dimethylamino group, an N,N-diethylamino group, an N,N-dipropylaminogroup, an N,N-diisopropylamino group, an N-methyl-N-ethylamino group, anN-methyl-N-propylamino group, an N-methyl-N-isopropylamino group and thelike.

The “hydroxy-lower alkyl-amino group” in Formula (I) means anN-mono-substituted or N,N-disubstituted, preferably N-mono-substitutedamino group with the “hydroxy-lower alkyl group”, and examples thereofinclude a hydroxymethylamino group, a 2-hydroxyethylamino group, a1-hydroxy-1-methylethylamino group, a 1,2-dihydroxyethylamino group, a3-hydroxypropylamino group and the like.

The “mono-lower alkyl-carbamoyl group” in Formula (I) means a group inwhich a nitrogen atom of the carbamoyl group is N-mono-substituted withthe “lower alkyl group”, and examples thereof include anN-methylcarbamoyl group, an N-ethylcarbamoyl group, an N-propylcarbamoylgroup, an N-isopropylcarbamoyl group, an N-butylcarbamoyl group, anN-sec-butylcarbamoyl group, an N-tert-butylcarbamoyl group and the like.

The “di-lower alkyl-carbamoyl group” in Formula (I) means a group inwhich the nitrogen atom of the carbamoyl group is N,N-disubstituted withthe “lower alkyl groups” that are identical or different, and examplesthereof include an N,N-dimethylcarbamoyl group, an N,N-diethylcarbamoylgroup, an N-ethyl-N-methylcarbamoyl group, an N,N-dipropylcarbamoylgroup, an N-methyl-N-propylcarbamoyl group, an N,N-diisopropylcarbamoylgroup and the like.

In addition, the “di-lower alkyl-carbamoyl group” also includes a5-membered to 8-membered monocycle formed by joining of the nitrogenatom constituting the carbamoyl group and the “lower alkyl groups” thatare identical or different and bonded to the nitrogen atom, or a dicycleformed by condensation of the monocycle and a benzene ring or a pyridinering, and examples thereof include groups represented by the formulaedescribed below.

The “lower alkanoylamino group” in Formula (I) means a group in whichthe “lower alkanoyl group” and an amino group or the “lower alkyl-aminogroup” are bonded to each other, and examples thereof include anN-acetylamino group, an N-propanoylamino group, an N-butanoylaminogroup, an N-pentanoylamino group, an N-pivaloyl group, anN-methyl-N-acetylamino group, an N-methyl-N-propanoylamino group, anN-methyl-N-butanoylamino group, an N-methyl-N-pentanoylamino group, anN-ethyl-N-acetylamino group, an N-ethyl-N-propanoylamino group, anN-ethyl-N-butanoylamino group, an N-ethyl-N-pentanoylamino group and thelike.

The “lower alkoxy-carbonylamino group” in Formula (I) means a group inwhich the “lower alkoxy-carbonyl group” is bonded to an amino group orthe “lower alkyl-amino group”, and examples thereof include amethoxycarbonylamino group, an ethoxycarbonylamino group, apropoxycarbonylamino group, an isopropoxycarbonylamino group, abutoxycarbonylamino group, an isobutoxycarbonylamino group, asec-butoxycarbonylamino group, a tert-butoxycarbonylamino group, apentyloxycarbonylamino group, a neopentyloxycarbonylamino group, ahexyloxycarbonylamino group, an isohexyloxycarbonylamino group, anN-methyl-methoxycarbonylamino group, an N-methyl-ethoxycarbonylaminogroup and the like.

The “lower alkyl-sulfonylamino group” in Formula (I) means a group inwhich the “lower alkyl-sulfonyl group” is bonded to an amino group orthe “lower alkyl-amino group”, and examples thereof include amethylsulfonylamino group, an ethylsulfonylamino group, apropylsulfonylamino group, an isopropylsulfonylamino group, abutylsulfonylamino group, a sec-butylsulfonylamino group, atert-butylsulfonylamino group, an N-methyl-methylsulfonylamino group, anN-methyl-ethylsulfonylamino group, an N-methyl-propylsulfonylaminogroup, an N-methyl-isopropylsulfonylamino group, anN-methyl-butylsulfonylamino group, an N-methyl-sec-butylsulfonylaminogroup, an N-methyl-tert-butylsulfonylamino group, anN-ethyl-methylsulfonylamino group, an N-ethyl-ethylsulfonylamino group,an N-ethyl-propylsulfonylamino group, an N-ethyl-isopropylsulfonylaminogroup, an N-ethyl-butylsulfonylamino group, anN-ethyl-sec-butylsulfonylamino group, an N-ethyl-tert-butylsulfonylaminogroup and the like.

Examples of the “aryl group” in Formula (I) include a phenyl group, anaphthyl group, a biphenyl group, an anthryl group and the like.

The “heteroaryl group” in Formula (I) means a 5-membered or 6-memberedmonocycle containing 1 or 2, or more, preferably 1 to 4 heteroatoms thatare identical or different and selected from the group consisting of anoxygen atom, a nitrogen atom and a sulfur atom, or means a dicycleobtained by condensation of the monocycle and a benzene ring or apyridine ring, and examples thereof include a pyrrolyl group, a furylgroup, a thienyl group, an imidazolyl group, a pyrazolyl group, athiazolyl group, an isothiazolyl group, a oxazolyl group, an isoxazolylgroup, a triazolyl group, a tetrazolyl group, a 1,2,3-oxadiazolyl group,a 1,2,4-oxadiazolyl group, a 1,3,4-oxadiazolyl group, a1,2,5-oxadiazolyl group, a 1,2,3-thiadiazolyl group, a1,2,4-thiadiazolyl group, a 1,3,4-thiadiazolyl group, a1,2,5-thiadiazolyl group, a pyridyl group, a pyrazinyl group, apyrimidinyl group, a pyridazinyl group, a 1,2,4-triazinyl group, a1,3,5-triazinyl group, an indolyl group, an isoindolyl group, abenzofuranyl group, a benzothienyl group, a benzoimidazolyl group, abenzoxazolyl group, a benzoisoxazolyl group, a benzothiazolyl group, abenzoisothiazolyl group, an indazolyl group, an imidazopyridyl group, apurinyl group, a quinolyl group, a quinolizinyl group, an isoquinolylgroup, a phthalazinyl group, a naphthyridinyl group, a quinoxalinylgroup, a quinazolinyl group, a cinnolinyl group, a pteridinyl group, apyrido[3,2-b]pyridyl group and the like.

The “aliphatic heterocyclic group” in Formula (I) means a 5-membered or6-membered monocycle containing 1 or 2, or more heteroatoms that areidentical or different and selected from the group consisting of anoxygen atom, a nitrogen atom and a sulfur atom, or means a saturated orunsaturated aliphatic heterocyclic group that is a fused ring composedof two rings to three rings containing the heteroatoms, and examplesthereof include an azetidil group, a pyrrolidinyl group, a piperidinylgroup, a pyrazinyl group, a morpholino group, a tetrahydrofuranyl group,an imidazolidinyl group, a thiomorpholino group, a tetrahydroquinolylgroup, a tetrahydroisoquinolyl group and the like.

The “aryloxy group” in Formula (I) means a group in which an oxygen atomis bonded to the “aryl group”, and examples thereof include a phenoxygroup, a Naphthalene-1-yloxy group, a Naphthalene-2-yloxy group and thelike.

The “heteroaryloxy group” in Formula (I) means a group in which anoxygen atom is bonded to the “heteroaryl group”, and examples thereofinclude a furan-2-yloxy group, a furan-3-yloxy group, athiophene-2-yloxy group, a thiophene-3-yloxy group, a 1H-pyrrol-2-yloxygroup, a 1H-pyrrol-3-yloxy group, a 1H-imidazole-2-yloxy group, a1H-imidazole-4-yloxy group, a 3H-imidazole-4-yloxy group, a4H-[1,3,4]triazole-3-yloxy group, a 2H-[1,2,4]triazole-3-yloxy group, a1H-[1,2,4]triazole-3-yloxy group, a thiazole-2-yloxy group, athiazole-4-yloxy group, a thiazole-5-yloxy group, a pyridin-2-yloxygroup, a pyridin-3-yloxy group, a pyridin-4-yloxy group, apyrimidin-2-yloxy group, a pyrimidin-4-yloxy group, a pyrimidin-5-yloxygroup, a pyridazin-3-yloxy group, a pyridazin-4-yloxy group, a2H-pyrazole-3-yloxy group, a 1H-pyrazole-4-yloxy group, a1H-pyrazole-3-yloxy group, a pyrazinyloxy group, a quinoline-2-yloxygroup, a quinoline-3-yloxy group, a quinoline-4-yloxy group, anisoquinoline-1-yloxy group, an isoquinoline-3-yloxy group, anisoquinoline-4-yloxy group, a quinazolin-2-yloxy group, aquinazolin-3-yloxy group, a quinoxalin-2-yloxy group, aquinoxalin-3-yloxy group, a cinnolin-3-yloxy group, a cinnolin-4-yloxygroup, a 1H-benzoimidazole-2-yloxy group, a1H-imidazo[4,5-b]pyridin-5-yloxy group, a1H-imidazo[4,5-b]pyridin-6-yloxy group, a1H-imidazo[4,5-b]pyridin-7-yloxy group, a benzo[d]isoxazole-4-yloxygroup, a benzo[d]isoxazole-5-yloxy group, a benzo[d]isoxazole-6-yloxygroup, a benzoxazol-4-yloxy group, a benzoxazol-5-yloxy group, abenzoxazol-6-yloxy group and the like.

The “lower alkylene group” in Formula (I) means a C₁₋₆ straight orbranched alkylene group, and examples thereof include a methylene group,an ethylene group, a trimethylene group, a tetramethylene group, apentamethylene group, a hexamethylene group and the like.

The “lower alkenylene group” in Formula (I) means a divalent groupformed by removing hydrogen atoms each from both ends of the chain ofthe “lower alkenyl group”, and examples thereof include a vinylenegroup, a propenylene group and the like.

The “lower alkynylene group” in Formula (I) means a divalent groupformed by removing hydrogen atoms each from both ends of the chain ofthe “lower alkynyl group”, and examples thereof include an ethynylenegroup, a propynylene group and the like.

The “lower alkylenedioxy group” in Formula (I) means a group formed byrespective bonding of the both ends of the “lower alkylene group” to anoxygen atom, and examples thereof include a methylenedioxy group, anethylenedioxy group, a propylenedioxy group and the like.

The “lower alkenyl group” in Formula (I) means a C₂₋₆ straight orbranched alkenyl group, and examples thereof include a vinyl group, a1-propenyl group, an allyl group, an isopropenyl group, a 3-butenylgroup, a 2-butenyl group, a 1-butenyl group, a 1-methyl-2-propenylgroup, a 1-methyl-1-propenyl group, a 1-ethyl-1-ethenyl group, a2-methyl-2-propenyl group, a 2-methyl-1-propenyl group, a3-methyl-2-butenyl group, a 4-pentenyl group and the like.

The “lower alkynyl group” in Formula (I) means a C₂₋₆ straight orbranched alkynyl group, and examples thereof include an ethynyl group, a1-propynyl group, a 2-propynyl group, a 3-butynyl group, a 2-butynylgroup, a 1-butynyl group, a 1-methyl-2-propynyl group, a1-ethyl-2-propynyl group, a 1-methyl-2-butynyl group, a 4-pentynyl groupand the like.

The “aralkyl group” in Formula (I) means the “lower alkyl group” inwhich any substitutable position is substituted with 1 or 2, or more,preferably 1 or 2 of the “aryl groups”, and examples thereof include abenzyl group, a 1-phenylethyl group, a 2-phenylethyl group and1-naphtylmethyl group, a 2-naphtylmethyl group and the like.

The “any substitutable position” used in this specification means a siteof a substitutable hydrogen atom on a carbon atom, a nitrogen atom, anoxygen atom and/or a sulfur atom, wherein the substitution of thehydrogen atom is chemically accepted, and as a result, results in astable compound.

Various symbols used in Formula (I) and the like will be furtherdescribed in detail with preferable embodiments thereof in order tofurther specifically disclose the compound of the present invention.

R¹ in Formula (I) is a lower alkyl group that may be substituted with acycloalkyl group, a cycloalkyl group, a halo-lower alkyl group, ahydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a loweralkoxy-carbonyl group, a lower alkyl-sulfonyl group or a grouprepresented by the general formula: -Q¹-A¹.

R¹ is preferably, for example, a lower alkyl group that may besubstituted with a cycloalkyl group, a cycloalkyl group, a loweralkyl-sulfonyl group, or a group represented by the general formula:-Q¹-A¹ and the like, more preferably a group represented by the generalformula: -Q¹-A¹ and the like.

“A lower alkyl group that may be substituted with a cycloalkyl group”indicated by R¹ means an unsubstituted lower alkyl group, or a loweralkyl group in which any substitutable position is substituted with 1 or2 or more, preferably 1 or 2 of the “cycloalkyl group” referred to inthe above that are identical or different, and examples of the grouppreferably include a methyl group, an ethyl group, a propyl group, anisopropyl group, a butyl group, an isobutyl group, a sec-butyl group, atert-butyl group, a pentyl group, an isopentyl group, an isoamyl group,a neopentyl group, a 1,1-dimethylpropyl group, a 1-methylbutyl group, a2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group, anisohexyl group, 1-methylpentyl group, 2-methylpentyl group, a3-methylpentyl group, an 1,1-dimethylbutyl group, a 1,2-dimethylbutylgroup, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a2,3-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1-ethylbutylgroup, a 2-ethylbutyl group, a 1,2,2-trimethyl propyl group, a1-ethyl-3-methylpropyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentyl methyl group, a cyclohexyl methyl group, acycloheptyl methyl group, a 1-cyclopropylethyl group, a 1-cyclobutylethyl group, a 1-cyclopentyl ethyl group, a 1-cyclohexyl ethyl group, a1-cycloheptyl ethyl group, a 2-cyclopropylethyl group, a 2-cyclobutylethyl group, a 2-cyclopentyl ethyl group, a 2-cyclohexyl ethyl group, a2-cycloheptyl ethyl group, and the like, and more preferably, anisopropyl group, an isobutyl group, a cyclopropylmethyl group, acyclobutyl methyl group, a cyclopentyl methyl group, a cyclohexyl methylgroup, and the like.

The cycloalkyl group of R¹ is preferably, for example, a cyclopropylgroup, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group andthe like.

The halo-lower alkyl group of R¹ is preferably, for example, afluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a2,2,2-trifluoroethyl group and the like.

The hydroxy-lower alkyl group of R¹ is preferably, for example, ahydroxymethyl group, a 2-hydroxyethyl group and the like.

The lower alkoxy-lower alkyl group of R¹ is preferably, for example, amethoxymethyl group, an ethoxymethyl group and the like.

The lower alkoxy-carbonyl group of R¹ is preferably, for example, amethoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group,an isopropoxycarbonyl group, a butoxycarbonyl group, anisobutoxycarbonyl group, a tert-butoxycarbonyl group, apentyloxycarbonyl group and the like.

The lower alkyl-sulfonyl group of R¹ is preferably, for example, amethanesulfonyl group, an ethanesulfonyl group and the like.

Q¹ represents a single bond or a lower alkylene group (herein 1 or 2, ormore methylene groups constituting the lower alkylene group eachindependently may be substituted with a carbonyl group, a sulfinyl groupor a sulfonyl group for the total methylene groups, and/or the hydrogenconstituting the methylene group may be substituted with a lower alkylgroup.).

The lower alkylene group of Q¹ is preferably, for example, a methylenegroup, an ethylene group, a trimethylene group and the like.

1 or 2, or more of the methylene groups constituting the lower alkylenegroup of Q¹ each independently may be substituted with a carbonyl group,a sulfinyl group or a sulfonyl group for the total methylene groups,and/or the hydrogen constituting the methylene group may be substitutedwith a lower alkyl group, and such substitutable or substituted group ispreferably, for example, a group selected from the formulae describedbelow.

A¹ represents an aryl group or a heteroaryl group, which may besubstituted with one to three substituents selected from the<Substituent group L> (herein any two substituents adjacent to eachother on the aryl group or the heteroaryl group may join together toform a lower alkylenedioxy group.).

In this case, <Substituent group L> is the group consisting of a halogenatom, a hydroxyl group, a nitro group, a cyano group, a formyl group, anamino group, a carboxyl group, a lower alkyl group, a halo-lower alkylgroup, a cycloalkyl group, a lower alkoxy group, a halo-lower alkoxygroup, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, alower alkoxycarbonyl group, a lower alkanoyl group, a lower alkylthiogroup, a lower alkylsulfonyl group, a lower alkylamino group, a di-loweralkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group,a di-lower alkyl carbamoyl group, a lower alkanoylamino group, a loweralkylsulfonylamino group, a lower alkoxycarbonylamino group, an aralkylgroup, an aryloxy group, a heteroaryloxy group, and a lower alkenylgroup.

The aryl group indicated by A¹ is, preferably, for example, a phenylgroup, a naphthyl group, a biphenyl group and the like.

The heteroaryl group of A¹ is, for example, an imidazolyl group, a furylgroup, a thienyl group, a pyrazolyl group, a thiazolyl group, anisothiazolyl group, an oxazolyl group, an isoxazolyl group, a1,2,4-oxadiazolyl group, a 1,3,4-oxadiazolyl group, a pyridyl group, apyrazinyl group, a pyrimidinyl group, a benzofuranyl group, a quinolylgroup, a benzothienyl group, and the like, more preferably, a pyridylgroup, a quinolyl group, a thienyl group, a pyrazolyl group, a thiazolylgroup, an isoxazolyl group, a benzothienyl group, and the like, andfurther preferably, a pyridyl group, an isoxazolyl group, a quinolylgroup, and a benzothienyl group and the like.

The “any two substituents adjacent to each other on the aryl group orthe heteroaryl group may join together to form a lower alkylenedioxygroup” of A¹ refers to a lower alkylenedioxy group formed by joining ofany two substituents adjacent to each other on the aryl group or theheteroaryl group, and is preferably, for example, a benzo[1,3]dioxolylgroup, a 2,3-dihydro-benzo[1,4]dioxynyl group and the like.

Therefore, examples of A¹ include, for example, a phenyl group, a2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group,2,3-difluorophenyl group, a 2,4-difluorophenyl group, a2,5-difluorophenyl group, a 2,6-difluorophenyl group, a3,4-difluorophenyl group, a 3,5-difluorophenyl group, a 2-chlorophenylgroup, a 3-chlorophenyl group, a 4-chlorophenyl group, a2,3-dichlorophenyl group, a 2,4-dichlorophenyl group, a2,5-dichlorophenyl group, a 2,6-dichlorophenyl group, a 2-bromophenylgroup, a 3-bromophenyl group, a 4-bromophenyl group, a2-chloro-3-fluorophenyl group, a 2-chloro-4-fluorophenyl group, a2-chloro-5-fluorophenyl group, a 2-chloro-6-fluorophenyl group, a2-bromo-3-fluorophenyl group, a 2-bromo-4-fluorophenyl group, a2-bromo-5-fluorophenyl group, a 2-bromo-6-fluorophenyl group, a2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a2-ethylphenyl group, a 3-ethylphenyl group, a 4-ethylphenyl group, a2-cyclopropylphenyl group, a 3-cyclopropylphenyl group, a4-cyclopropylphenyl group, a 2-trifluoromethylphenyl group, a3-trifluoromethylphenyl group, a 4-trifluoromethylphenyl group, a2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group,a 2-difluoromethoxyphenyl group, a 3-difluoromethoxyphenyl group, a4-difluoromethoxyphenyl group, a 2-trifluoro methoxyphenyl group, a3-trifluoromethoxyphenyl group, a 4-trifluoromethoxyphenyl group, a2-hydroxyphenyl group, a 3-hydroxyphenyl group, a 4-hydroxyphenyl group,a 2-hydroxy methylphenyl group, a 3-hydroxy methylphenyl group, a4-hydroxy methylphenyl group, a 2,4-dimethylphenyl group, a2,5-dimethylphenyl group, a 2,6-dimethylphenyl group, a2,4,6-trimethylphenyl group, a 2-fluoro-6-trifluoro methylphenyl group,a 4-fluoro-2-trifluoro methylphenyl group, a benzo[1,3]dioxo-5-yl group,a 6-chlorobenzo[1,3]dioxo-5-yl group, a 1-naphthyl group, a 2-naphthylgroup, a 2-biphenyl group, a 3-biphenyl group, a 4-biphenyl group, a2-phenoxy group, a 3-phenoxy group, a 4-phenoxy group, a 2-imidazolylgroup, a 2-furyl group, a 2-thienyl group, a 1,2,4-oxadiazol-5-yl group,a 1,3,4-oxadiazol-2-yl group, a 1,2,4-thiadiazole-5-yl group, a1,3,4-thiadiazole-2-yl group, a 4-isoxazolyl group, a3,5-dimethylisoxazolyl group, a 2-pyridyl group, a 3-pyridyl group, a4-pyridyl group, a 2-fluoro-5-pyridyl group, a 3-fluoro-6-pyridyl group,a 2-chloro-3-pyridyl group, a 2-chloro-5-pyridyl group, a2-methyl-3-pyridyl group, a 2-methyl-6-pyridyl group, a 2-pyrimidinylgroup, a 4-benzo[b]furanyl group, a 7-benzo[b]furanyl group, a2-quinolyl group, a 3-quinolyl group, a 4-quinolyl group, a 5-quinolylgroup, a 6-quinolyl group, a 8-quinolyl group, a 5-chlorothiophene-2-ylgroup, a 2-benzo[b]thiophenyl group, a 3-benzo[b]thiophenyl group, a4-benzo[b]thiophenyl group, a 5-benzo[b]thiophenyl group, a6-benzo[b]thiophenyl group, a 7-benzo[b]thiophenyl group, a5-chlorobenzo[b]thiophene-3-yl group, a 2-chloro-6-methylphenyl group, a2-chloro-6-cyclopropyl phenyl group, a 2-chloro-6-cyanophenyl group, a2,6-dicyclopropyl phenyl group, and the like, and among them,preferably, a 2-fluorophenyl group, a 3-fluorophenyl group, a2,3-difluorophenyl group, a 2,4-difluorophenyl group, a2,5-difluorophenyl group, a 2,6-difluorophenyl group, a 2-chlorophenylgroup, a 2,3-dichlorophenyl group, a 2,6-dichlorophenyl group, a2-bromophenyl group, a 2-chloro-3-fluorophenyl group, a2-chloro-4-fluorophenyl group, a 2-chloro-5-fluorophenyl group, a2-chloro-6-fluorophenyl group, a 2-bromo-3-fluorophenyl group, a2-bromo-4-fluorophenyl group, a 2-bromo-5-fluorophenyl group, a2-bromo-6-fluorophenyl group, a 2-methylphenyl group, a 2-trifluoromethylphenyl group, a 2-methoxyphenyl group, a 2-difluoromethoxyphenylgroup, a 2-trifluoromethoxyphenyl group, a 2-hydroxyphenyl group, a2-hydroxymethylphenyl group, a 2,4-dimethylphenyl group, a2,5-dimethylphenyl group, a 2,6-dimethylphenyl group, a2,4,6-trimethylphenyl group, a 2,3-dichlorophenyl group, a2,6-dichlorophenyl group, a 2-fluoro-6-trifluoro methylphenyl group, a2-trifluoro-4-fluorophenyl group, a 1-naphthyl group, a 8-quinolylgroup, a 6-chlorobenzo[1,3]dioxo-5-yl group, a5-chlorobenzo[b]thiophene-3-yl group, a 2-chloro-6-methylphenyl group, a2-chloro-6-cyclopropylphenyl group, a 2-chloro-6-cyanophenyl group, andthe like, and particularly preferably, a 2-chlorophenyl group, a2,3-dichlorophenyl group, a 2,6-dichlorophenyl group, a2-chloro-6-fluorophenyl group, a 2,5-dimethylphenyl group, a2,6-dimethylphenyl group, a 2,4,6-trimethyl phenyl group, a 1-naphthylgroup, a 8-quinolyl group, a 6-chlorobenzo[1,3]dioxo-5-yl group, a5-chlorobenzo[b]thiophene-3-yl group, a 2-chloro-6-methylphenyl group, a2-chloro-6-cyclopropyl phenyl group, and a 2-chloro-6-cyanophenyl group,and the like.

represents a double bond or a single bond,

when

is a double bond,

W¹ represents a nitrogen atom or a group represented by the generalformula: ═C(R^(a))—, and

W² represents a nitrogen atom or a group represented by the generalformula: ═C(R^(b))—,

when

is a single bond,

W¹ represents a group represented by the general formula:—C(R^(aa))(R^(ab))—, or a group represented by the general formula:—(C═O)—, and

W² represents a group represented by the general formula:—C(R^(ba))(R^(bb))—, a group represented by the general formula: —(C═O)—or a group represented by the general formula: —N(R^(bc))—.

Herein, the substructure of General Formula (I):

is exemplified as follows in relation to W

W².

More preferably, the substructure of General Formula (I) is selectedfrom the followings.

R^(a) and R^(b) represent each independently a hydrogen atom, asubstituent selected from the <Substituent group M> or a grouprepresented by the general formula: -Q²-A².

Herein, <Substituent group M> is the group consisting of a halogen atom,a hydroxyl group, a nitro group, a cyano group, a formyl group, an aminogroup, a carboxyl group, a lower alkyl group, a halo-lower alkyl group,a cycloalkyl group, a lower alkoxy group, a halo-lower alkoxy group, ahydroxy lower alkyl group, a lower alkoxy lower alkyl group, a loweralkoxycarbonyl group, a lower alkanoyl group, a lower alkylthio group, alower alkylsulfonyl group, a lower alkylamino group, a di-loweralkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group,a di-lower alkyl carbamoyl group, a lower alkanoylamino group, a loweralkylsulfonylamino group, and a lower alkoxycarbonylamino group.

R^(a) and R^(b) are preferably, for example, a hydrogen atom, a halogenatom, a hydroxyl group, a cyano group, a formyl group, a carboxyl group,a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, ahydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a loweralkoxy-carbonyl group, a lower alkanoyl group and a group represented bythe general formula: -Q²-A² and the like, and more preferably, ahydrogen atom, a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a cycloalkyl group, a lower alkanoyl group and agroup represented by the general formula: -Q²-A² and the like.

R^(aa) and R^(ab) are each independently a hydrogen atom, a substituentselected from the <Substituent group N> or a group represented by thegeneral formula: -Q²-A².

<Substituent group N> is the group consisting of a hydroxyl group, acyano group, a formyl group, a carboxyl group, a lower alkyl group, ahalo-lower alkyl group, a cycloalkyl group, a lower alkoxy group, ahalo-lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxylower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group,a carbamoyl group, a mono-lower alkyl carbamoyl group, and a di-loweralkyl carbamoyl group.

Alternatively, R^(aa) and R^(ab) may join together to form a loweralkylene group (herein 1 to 2 or more methylene groups constituting thelower alkylene group each independently may be substituted with anoxygen atom, a carbonyl group, a vinylene group or a group representedby the general formula: —N(R^(c))— for the total methylene groups,and/or the hydrogen constituting the methylene group may be substitutedwith a hydroxyl group, a lower alkyl group or a halogen atom.).

The “R^(aa) and R^(ab) may join together to form a lower alkylene group”refers that the carbon atoms substituted with R^(aa) and R^(ab) arebonded to each other via the lower alkylene group, whereby to form asaturated 3-membered to 7-membered, cyclocarbocyclic ring. Herein, 1 to2 or more methylene groups constituting the lower alkylene group eachindependently may be substituted with an oxygen atom, a carbonyl group,a vinylene group or a group represented by the general formula:—N(R^(c))— for the total methylene groups, and/or the hydrogenconstituting the methylene group may be substituted with a hydroxylgroup, a lower alkyl group or a halogen atom. For example, a cyclopropylgroup, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group andthe like are preferable.

R^(aa) and R^(ab) are preferably, for example, a hydrogen atom, a loweralkyl group, a halo-lower alkyl group, a cycloalkyl group, a loweralkoxy group and a group represented by the general formula: -Q²-A² andthe like.

R^(ba) and R^(bb) represent each independently a hydrogen atom, ahalogen atom, an amino group, a lower alkyl-amino group, a di-loweralkyl-amino group, a hydroxy-lower alkyl-amino group, a loweralkyl-sulfonylamino group, a lower alkoxy-carbonylamino group, asubstituent selected from the <Substituent group N> or a grouprepresented by the general formula: -Q²-A².

Alternatively, R^(ba) and R^(bb) may join together to form a loweralkylene group (herein 1 to 2 or more methylene groups constituting thelower alkylene group each independently may be substituted with anoxygen atom, a carbonyl group, a vinylene group or a group representedby the general formula: —N(R^(c))— for the total methylene groups,and/or may be substituted with a hydroxyl group, a lower alkyl group ora halogen atom.).

The “R^(ba) and R^(bb) may join together to form a lower alkylene group”refers that the carbon atoms substituted with R^(ba) and R^(bb) arebonded to each other via the lower alkylene group, whereby to form asaturated 3-membered to 7-membered, cyclocarbocyclic ring. Herein, 1 to2 or more methylene groups constituting the lower alkylene group eachindependently may be substituted with an oxygen atom, a carbonyl group,a vinylene group or a group represented by the general formula:—N(R^(c))— for the total methylene groups, and/or the hydrogenconstituting the methylene group may be substituted with a hydroxylgroup, a lower alkyl group or a halogen atom. For example, a cyclopropylgroup, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group andthe like are preferable.

R^(ba) and R^(bb) are preferably, for example, a hydrogen atom, ahalogen atom, a lower alkyl-amino group, a di-lower alkyl-amino group, alower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a loweralkoxy group, a lower alkoxy-carbonyl group, a lower alkanoyl group, acarbamoyl group, a mono-lower alkyl-carbamoyl group and a di-loweralkyl-carbamoyl group and a group represented by the general formula:-Q²-A² and the like.

R^(bc) represents a substituent selected from the group consisting of ahydrogen atom, a lower alkyl group, a cycloalkyl group, a halo-loweralkyl group, a lower alkoxy-carbonyl group, a carbamoyl group, amono-lower alkyl-carbamoyl group, a di-lower alkyl-carbamoyl group and alower alkanoyl group or a group represented by the general formula:-Q²-A².

R^(bc) is preferably, for example, a hydrogen atom, a lower alkyl group,a halo-lower alkyl group, a lower alkanoyl group and a group representedby the general formula: -Q²-A² and the like.

Q² represents a single bond, a lower alkylene group or a loweralkenylene group, wherein 1 or 2, or more methylene groups constitutingthe lower alkylene group each independently may be substituted with anoxygen atom, a nitrogen atom or a carbonyl group for the total methylenegroups, and/or the hydrogen constituting the methylene group may besubstituted with a halogen atom, a cyano group, a hydroxyl group or alower alkyl group.

The lower alkylene group of Q² is preferably, for example, a methylenegroup, an ethylene group, a trimethylene group and the like.

1 or 2, or more of the methylene groups constituting the lower alkylenegroup of Q² each independently may be substituted with an oxygen atom, anitrogen atom or a carbonyl group for the total methylene groups, and/orthe hydrogen constituting the methylene group may be substituted with ahalogen atom, a cyano group, a hydroxyl group or a lower alkyl group.Such substitutable or substituted group is preferably, for example, agroup selected from the formulae described below.

Q² is more preferably a single bond, a methylene group and a groupselected from those described below and the like.

A² represents a cycloalkyl group, an aliphatic heterocyclic group, anaryl group or a heteroaryl group, which may be substituted with one tothree substituents selected from the <Substituent group L> (herein anytwo substituents adjacent to each other on the aryl group or theheteroaryl group may join together to form a lower alkylenedioxygroup.).

The aryl group of A² is preferably, for example, a phenyl group, anaphthyl group, a biphenyl group and the like.

The heteroaryl group of A² is preferably, for example, imidazolyl group,a furyl group, a thienyl group, a pyrazolyl group, a thiazolyl group, anisothiazolyl group, a oxazolyl group, an isoxazolyl group, a1,2,4-oxadiazolyl group, a 1,3,4-oxadiazolyl group, a pyridyl group, apyrazinyl group, a pyrimidinyl group, a benzofuranyl group, a quinolylgroup and the like, more preferably, a pyridyl group, a quinolyl groupand the like, and further preferably a pyridyl group and the like.

The “any two substituents adjacent to each other on the aryl group orthe heteroaryl group may join together to form a lower alkylenedioxygroup” of A² refers that any two substituents adjacent to each other onthe aryl group or the heteroaryl group join to form a loweralkylenedioxy group. For example, a benzo[1,3]dioxolyl group, a2,3-dihydro-benzo[1,4]dioxynyl group and the like are preferable.

Therefore, A² is, preferably, a phenyl group, a 2-fluorophenyl group, a3-fluorophenyl group, a 4-fluorophenyl group, a 2,3-difluorophenylgroup, a 2,4-difluorophenyl group, a 2,5-difluorophenyl group, a2,6-difluorophenyl group, a 3,4-difluorophenyl group, a3,5-difluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenylgroup, a 4-chlorophenyl group, a 2-bromophenyl group, a 3-bromophenylgroup, a 4-bromophenyl group, a 2-chloro-3-fluorophenyl group, a2-chloro-4-fluorophenyl group, a 2-chloro-5-fluorophenyl group, a2-chloro-6-fluorophenyl group, a 2-bromo-3-fluorophenyl group, a2-bromo-4-fluorophenyl group, a 2-bromo-5-fluorophenyl group, a2-bromo-6-fluorophenyl group, a 2-methylphenyl group, a 3-methylphenylgroup, a 4-methylphenyl group, a 2-trifluoromethylphenyl group, a3-trifluoromethylphenyl group, a 4-trifluoromethylphenyl group, a2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group,a 2-difluoromethoxyphenyl group, a 3-difluoromethoxyphenyl group, a4-difluoromethoxyphenyl group, a 2-trifluoromethoxyphenyl group, a3-trifluoro methoxyphenyl group, a 4-trifluoromethoxyphenyl group, a2-hydroxyphenyl group, a 3-hydroxyphenyl group, a 4-hydroxyphenyl group,a 2-hydroxymethylphenyl group, a 3-hydroxy methylphenyl group, a4-hydroxy methylphenyl group, a 2,6-dimethylphenyl group, a2,3-dichlorophenyl group, a 2,6-dichlorophenyl group, a2-fluoro-6-trifluoro methylphenyl group, a 2-trifluoro-4-fluorophenylgroup, a 2-imidazolyl group, a 2-furyl group, a 2-thienyl group, a1,2,4-oxadiazol-5-yl group, a 1,3,4-oxadiazol-2-yl group, a1,2,4-thiadiazole-5-yl group, a 1,3,4-thiadiazole-2-yl group, a2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a2-fluoro-5-pyridyl group, a 3-fluoro-6-pyridyl group, a 2-pyrimidinylgroup, a 4-benzo[b]furanyl group, a 7-benzo[b]furanyl group, a2-quinolyl group, a 3-quinolyl group, a 4-quinolyl group, a 5-quinolylgroup, a 6-quinolyl group, and a 8-quinolyl group, and the like.

W³, W⁴ and W⁵ represent each independently a nitrogen atom, or a methinegroup that may have a substituent selected from the group consisting ofa halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, acycloalkyl group, a halo-lower alkyl group, a lower alkoxy group and ahalo lower alkoxy group.

The “methine group that may have a substituent selected from the groupconsisting of halogen atom, a hydroxyl group, a cyano group, a loweralkyl group, a cycloalkyl group, a halo-lower alkyl group, a loweralkoxy group and a halo lower alkoxy group” means an unsubstitutedmethine group or a methine group that has a substituent. The substituentcan be selected from the group consisting of a halogen atom, a hydroxylgroup, a cyano group, a lower alkyl group, a cycloalkyl group, ahalo-lower alkyl group, a lower alkoxy group and a halo lower alkoxygroup.

The halogen atom of the substituent is preferably, for example, afluorine atom, a chlorine atom and the like.

The lower alkyl group of the substituent is preferably, for example, amethyl group, an ethyl group and the like.

The cycloalkyl group of the substituent is preferably, for example, acyclopropyl group and the like.

The halo-lower alkyl group of the substituent is preferably, forexample, a fluoromethyl group, a difluoromethyl group, a trifluoromethylgroup and the like.

The lower alkoxy group of the substituent is preferably, for example, amethoxy group, an ethoxy group and the like.

The halo lower alkoxy group of the substituent is preferably, forexample, a difluoromethoxy group, a trifluoromethoxy group and the like.

W¹, W², W³, W⁴ and W⁵ are such that 0 to 4, preferably 0 to 3,particularly preferably 0 to 2 of W¹, W², W³, W⁴ and W⁵ are nitrogenatoms.

X is a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, asulfonyl group, a carbonyl group, a lower alkenylene group, a loweralkynylene group or a group represented by the general formula:—N(R^(X))— (herein R^(X) is a hydrogen atom or a lower alkyl group.).

The lower alkenylene group of X is preferably, for example, a vinylenegroup and the like.

The lower alkynylene group of X is preferably, for example, anethynylene group and the like.

X is preferably, for example, a single bond, an oxygen atom, a carbonylgroup, a vinylene group and a group represented by the general formula:—N(R^(X))— and the like.

The lower alkyl group of R^(X) is preferably, for example, a methylgroup, an ethyl group, a propyl group and the like, more preferably amethyl group and the like.

Y is a single bond or (CR^(Yi)R^(Yi′))_(n) (herein n is any integer of 1to 6, i is any integer of 1 to n, and (CR^(Yi)R^(Yi′))_(n) represents(CR^(Y1)R^(Y1′)) when n=1; represents (CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))when n=2; represents (CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))—(CR^(Y3)R^(Y3′))when n=3; represents(CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))—(CR^(Y3)R^(Y3′))—(CR^(Y4)R^(Y4′)) whenn=4; represents(CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))—(CR^(Y3)R^(Y3′))—(CR^(Y4)R^(Y4′))—(CR^(Y5)R^(Y5′))when n=5, and represents(CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))—(CR^(Y3)R^(Y3′))—(CR^(Y4)R^(Y4′))—(CR^(Y5)R^(Y5′))—(CR^(Y6)R^(Y6′))when n=6.).

Y is preferably, for example, a single bond and (CR^(Yi)R^(Yi′))_(n)(herein n is any integer of 1 to 3, i is any integer of 1 to n, and(CR^(Yi)R^(Yi′))_(n) represents (CR^(Y1)R^(Y1′)) when n=1; represents(CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′)) when n=2, and represents(CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))—(CR^(Y3)R^(Y3′)) when n=3.).

R^(Y1), R^(Y1′), R^(Y2), R^(Y2′), R^(Y3), R^(Y3′), R^(Y4), R^(Y4′),R^(Y5), R^(Y5′), R^(Y6) and R^(Y6′) are each independently a hydrogenatom, a halogen atom or a substituent selected from the <Substituentgroup N>.

R^(Y1), R^(Y1′), R^(Y2), R^(Y2′), R^(Y3), R^(Y3′), R^(Y4), R^(Y4′),R^(Y5), R^(Y5′), R^(Y6) and R^(Y6′) are preferably each independently,for example, a hydrogen atom, a halogen atom, a hydroxyl group, a cyanogroup, a lower alkyl group, a lower alkoxy group and the like.

The lower alkyl group of the substituent is preferably, for example, amethyl group, an ethyl group and the like.

The lower alkoxy group of the substituent is preferably, for example, amethoxy group, an ethoxy group and the like.

In relation to R^(X), R^(Y1), R^(Y1′), R^(Y2), R^(Y2′), R^(Y3), R^(Y3′),R^(Y4), R^(Y4′), R^(Y5), R^(Y5′), R^(Y6) and R^(Y6′), the combinationsof the two groups below: (i) R^(Y1) and R^(Y1′), (ii) R^(Y2) andR^(Y2′), (iii) R^(Y3) and R^(Y3′), (iv) R^(Y4) and R^(Y4′), (v) R^(Y5)and R^(Y5′), (vi) R^(Y6) and R^(Y6′), (vii) R^(X) and R^(Y1), (viii)R^(X) and R^(Y2), (ix) R^(X) and R^(Y3), (x) R^(Y1) and R^(Y2), (xi)R^(Y1) and R^(Y3), (xii) R^(Y1) and R^(Y4), (xiii) R^(Y2) and R^(Y3),(xiv) R^(Y2) and R^(Y4) or (xv) R^(Y2) and R^(Y5), i.e., the two groupsconstituting the combinations may join together to form a lower alkylenegroup, wherein 1 or 2, or more methylene groups constituting the loweralkylene group each independently may be substituted with an oxygenatom, a carbonyl group, a vinylene group or the general formula—N(R^(c))— for the total methylene groups, and/or the hydrogenconstituting the methylene group may be substituted with a hydroxylgroup, a lower alkyl group or a halogen atom.

(i) The “R^(Y1) and R^(Y1′) join to form a lower alkylene group” refersthat the carbon atoms substituted with R^(Y1) and R^(Y1′) are bonded toeach other via the lower alkylene group, whereby to form a saturated3-membered to 7-membered, cyclocarbocyclic ring. For example, examplesthereof include a cyclopropyl group, a cyclobutyl group, a cyclopentylgroup, a cyclohexyl group and the like, and preferably a cyclopropylgroup and the like.

(ii) The “R^(Y2) and R^(Y2′) join to form a lower alkylene group” refersthat the carbon atoms substituted with R^(Y2) and R^(Y2′) are bonded toeach other via the lower alkylene group, whereby to form a saturated3-membered to 7-membered, cyclocarbocyclic ring. For example, examplesthereof include a cyclopropyl group, a cyclobutyl group, a cyclopentylgroup, a cyclohexyl group and the like, and preferably a cyclopropylgroup and the like.

(iii) The “R^(Y3) and R^(Y3′) join to form a lower alkylene group”refers that the carbon atoms substituted with R^(Y3) and R^(Y3′) arebonded to each other via the lower alkylene group, whereby to form asaturated 3-membered to 7-membered, cyclocarbocyclic ring. For example,examples thereof include a cyclopropyl group, a cyclobutyl group, acyclopentyl group, a cyclohexyl group, and the like, and preferably acyclopropyl group and the like.

(iv) The “R^(Y4) and R^(Y4′) join to form a lower alkylene group” refersthat the carbon atoms substituted with R^(Y4) and R^(Y4′) are bonded toeach other via the lower alkylene group, whereby to form a saturated3-membered to 7-membered, cyclocarbocyclic ring. For example, examplesthereof include a cyclopropyl group, a cyclobutyl group, a cyclopentylgroup, a cyclohexyl group, and the like, and preferably a cyclopropylgroup and the like.

(v) The “R^(Y5) and R^(Y5′) join to form a lower alkylene group” refersthat the carbon atoms substituted with R^(Y5) and R^(Y5′) are bonded toeach other via the lower alkylene group, whereby to form a saturated3-membered to 7-membered, cyclocarbocyclic ring. For example, examplesthereof include a cyclopropyl group, a cyclobutyl group, a cyclopentylgroup, a cyclohexyl group, and the like, and preferably a cyclopropylgroup and the like.

(vi) The “R^(Y6) and R^(Y6′) join to form a lower alkylene group” refersthat the carbon atoms substituted with R^(Y6) and R^(Y6′) are bonded toeach other via the lower alkylene group, whereby to form a saturated3-membered to 7-membered, cyclocarbocyclic ring. For example, examplesthereof include a cyclopropyl group, a cyclobutyl group, a cyclopentylgroup, a cyclohexyl group, and the like, and preferably a cyclopropylgroup and the like.

(vii) The “R^(X) and R^(Y1) join to form a lower alkylene group” refersthat R^(X) and R^(Y1) are bonded to each other via the lower alkylenegroup, whereby to form a saturated 3-membered to 7-membered,cyclocarbocyclic ring. For example, it is represented by the formuladescribed below.

(viii) The “R^(X) and R^(Y2) join to form a lower alkylene group” refersthat R^(X) and R^(Y2) are bonded to each other via the lower alkylenegroup, whereby to form a saturated 3-membered to 7-membered,cyclocarbocyclic ring. For example, it is represented by the formuladescribed below.

(ix) The “R^(X) and R^(Y3) join to form a lower alkylene group” refersthat R^(X) and R^(Y3) are bonded to each other via the lower alkylenegroup, whereby to form a saturated 3-membered to 7-membered,cyclocarbocyclic ring. For example, it is represented by the formuladescribed below.

(x) The “R^(Y1) and R^(Y2) join to form a lower alkylene group” refersthat R^(Y1) and R^(Y2) are bonded to each other via the lower alkylenegroup, whereby to form a saturated 3-membered to 7-membered,cyclocarbocyclic ring. For example, it is represented by the formuladescribed below.

(xi) The “R^(Y1) and R^(Y3) join to form a lower alkylene group” refersthat R^(Y1) and R^(Y3) are bonded to each other via the lower alkylenegroup, whereby to form a saturated 3-membered to 7-membered,cyclocarbocyclic ring. For example, it is represented by the formuladescribed below.

(xii) The “R^(Y1) and R^(Y4) join to form a lower alkylene group” refersthat R^(Y1) and R^(Y4) are bonded to each other via the lower alkylenegroup, whereby to form a saturated 3-membered to 7-membered,cyclocarbocyclic ring. For example, it is represented by the formuladescribed below.

(xiii) The “R^(Y2) and R^(Y3) join to form a lower alkylene group”refers that R^(Y2) and R^(Y3) are bonded to each other via the loweralkylene group, whereby to form a saturated 3-membered to 7-membered,cyclocarbocyclic ring. For example, it is represented by the formuladescribed below.

(xiv) The “R^(Y2) and R^(Y4) join to form a lower alkylene group” refersthat R^(Y2) and R^(Y4) are bonded to each other via the lower alkylenegroup, whereby to form a saturated 3-membered to 7-membered,cyclocarbocyclic ring. For example, it is represented by the formuladescribed below.

(xv) The “R^(Y2) and R^(Y5) join to form a lower alkylene group” refersthat R^(Y2) and R^(Y5) are bonded to each other via the lower alkylenegroup, whereby to form a saturated 3-membered to 7-membered,cyclocarbocyclic ring. For example, it is represented by the formuladescribed below.

1 or 2 or more of the methylene groups constituting the lower alkylenegroup forming the (i) to (xv) each independently may be substituted withan oxygen atom, a carbonyl group, a vinylene group or the generalformula: —N(R^(c))— for the total methylene groups, and/or the hydrogenconstituting the methylene group may be substituted with a hydroxylgroup, a lower alkyl group or a halogen atom.

R^(c) is a hydrogen atom, a lower alkyl group, a halo-lower alkyl groupor a lower alkanoyl group.

Accordingly, the combination of —X—Y— in General Formula (I) isexemplified as follows:

(1) when X is a single bond and Y is a single bond, General Formula (I)is represented by the formula described below.

(2) when X is a single bond and Y is (CR^(Yi)R^(Yi′))_(n), GeneralFormula (I) is represented by the formula described below.

(3) when X is an oxygen atom and Y is (CR^(Yi)R^(Yi′))_(n), GeneralFormula (I) is represented by the formula described below.

(4) when X is a carbonyl group and Y is (CR^(Yi)R^(Yi′))_(n), GeneralFormula (I) is represented by the formula described below.

(5) when X is a vinylene group and Y is a single bond, General Formula(I) is represented by the formula described below.

Z is a hydroxyl group, COOR², CONR³R⁴, SO₃R², SO₃NR³R⁴, a 5-tetrazolylgroup, a 5-oxo-1,2,4-oxadiazolyl group, a 2-oxo-1,3,4-oxadiazolyl group,a 5-imino-4,5-dihydro-1,3,4-oxadiazolyl group, a2-thioxo-1,3,4-oxadiazolyl group, or a 5-oxo-1,2,4-thiadiazolyl group.

R², R³, and R⁴ are each independently a hydrogen atom or a lower alkylgroup.

Preferable embodiments of the present invention can also be expressed as(1) to (9) described below.

(1) The compound of Formula (I), wherein the substructure describedbelow:

is selected from the followings:

or a pharmaceutically acceptable salt or ester of the compound.

(2) The compound or a pharmaceutically acceptable salt or ester of thecompound as described in the (1), wherein W³, W⁴, and W⁵ are eachindependently a nitrogen atom, or a methine group that may have asubstituent selected from the group consisting of a halogen atom and alower alkyl group.

(3) The compound or a pharmaceutically acceptable salt or ester of thecompound as described in the (2), wherein X is a single bond, an oxygenatom, a carbonyl group, a vinylene group or a group represented by thegeneral formula: —N(R^(X))—.

(4) The compound or a pharmaceutically acceptable salt or ester of thecompound as described in the (3), wherein R¹ is a group represented bythe general formula: -Q¹-A¹.

(5) The compound or a pharmaceutically acceptable salt or ester of thecompound as described in the (4), wherein Q¹ is a single bond or a loweralkylene group that may be substituted with a lower alkyl group.

(6) The compound or a pharmaceutically acceptable salt or ester of thecompound as described in the (5), wherein Y is a single bond or(CR^(Yi)R^(Yi′))_(n) (herein n is any integer of 1 to 6, i is anyinteger of 1 to n, and (CR^(Yi)R^(Yi′))_(n) represents (CR^(Y1)R^(Y1′))when n=1; represents (CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′)) when n=2;represents (CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))—(CR^(Y3)R^(Y3′)) when n=3;represents(CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))—(CR^(Y3)R^(Y3′))—(CR^(Y4)R^(Y4′)) whenn=4; represents(CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))—(CR^(Y3)R^(Y3′))—(CR^(Y4)R^(Y4′))—(CR^(Y5)R^(Y5′))when n=5; and represents(CR^(Y1)R^(Y1′))—(CR^(Y2)R^(Y2′))—(CR^(Y3)R^(Y3′))—(CR^(Y4)R^(Y4′))—(CR^(Y5)R^(Y5′))—(CR^(Y6)R^(Y6′))when n=6, wherein R^(Y1), R^(Y1′), R^(Y2), R^(Y2′), R^(Y3), R^(Y3′),R^(Y4), R^(Y4′), R^(Y5), R^(Y5′), R^(Y6) and R^(Y6′) are eachindependently a hydrogen atom, a halogen atom or a substituent selectedfrom the <Substituent group N>.

(7) The compound or a pharmaceutically acceptable salt or ester of thecompound as described in the (6), wherein Q¹ is a methylene group.

(8) The compound or a pharmaceutically acceptable salt or ester of thecompound as described in the (7), wherein the aryl group or theheteroaryl group of A¹ is a phenyl group, a naphthyl group, a pyridylgroup, a pyridanyzil group, a pyrazinyl group, a pyrimidinyl group, aquinolyl group, an isoquinolyl group, or a benzothienyl group.

(9) The compound or a pharmaceutically acceptable salt or ester of thecompound as described in the (8), wherein the <Substituent group L> isthe group consisting of a hydroxyl group, a halogen atom, a cyano group,a methyl group, an ethyl group, a cyclopropyl group, a trifluoromethylgroup, a hydroxymethyl group, a methoxy group, and a trifluoromethoxygroup.

A compound shown by the above-mentioned Formula (I) or pharmaceuticallyacceptable salt or ester includes, for example, a compound given in anexample, or a pharmaceutically acceptable salt or ester of the compound.Among them, compounds (a)-(s) provided below and a pharmaceuticallyacceptable salt or ester of the compound are more preferable:

-   (a) 1-(2,6-dimethylbenzyl)-3-methyl-1H-indole-6-carboxylic acid    (Example 61)-   (b) 2-[1-(2,6-dimethylbenzyl)-3-methyl-1H-indole-6-yl]acetic acid    (Example 64)-   (c) 2-[1-(2,6-dimethylbenzyl)-3-methyl-1H-indazole-6-yl]acetic acid    (Example 66)-   (d) 2-[3-chloro-1-(2,6-dimethylbenzyl)-1H-indole-6-yl]acetic acid    (Example 68)-   (e) 2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-1H-indole-6-yl]acetic acid    (Example 75)-   (f)    (3-RS)-2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3-methyl-1H-indole-6-yl]acetic    acid (Example 78)-   (g)    2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3,3-dimethyl-1H-indole-6-yl]acetic    acid (Example 80)-   (h) 2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indole-6-yl]acetic acid    (Example 82)-   (i) 2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]acetic acid    (Example 97)-   (j) 2-[1-(2-chloro-6-methylbenzyl)-3-methyl-1H-indazole-6-yl]acetic    acid (Example 102)-   (k) 3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]propionic    acid (Example 122)-   (l)    1-(2,6-dichlorobenzyl)-3-methyl-6-(1H-tetrazole-5-ylmethyl)-1H-indazole    (Example 134)-   (m) 2-[1-(2,6-dichlorobenzyl)-3-ethyl-1H-indazole-6-yl]acetic acid    (Example 140)-   (n)    1-(2-chloro-6-methylbenzyl)-3-methyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine    (Example 160)-   (o)    1-(2-chloro-6-cyclopropylbenzyl)-3-methyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine    (Example 164)-   (p)    3-chloro-1-(2,6-dichlorobenzyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxylic    acid (Example 172)-   (q)    3-chloro-1-(2-chloro-6-methylbenzyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxylic    acid (Example 174)-   (r)    3-chloro-1-(2-chloro-6-methylbenzyl)-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine    (Example 177)-   (s) [1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]difluoroacetic    acid (Example 183).

The compound of the present invention may have an asymmetrical center, achiral axis, and a chiral plane.

The compound of the present invention may occur as a racemate, a racemicmixture, and an individual diastereomer.

In addition, all possible isomers including optical isomers, andmixtures thereof are all included in the present invention.

Further, the compound disclosed in the present specification may bepresent as a tautomer, and although the compound is depicted as only onetautomer structure, both tautomer types are intended to be encompassedby the scope of the present invention.

The substitution in, for example, an oxygen atom, a carbonyl group, avinylene group or a group represented by the general formula: —N(R^(c))—of the methylene group constituting the lower alkylene group in thepresent invention is accepted when the substitution is chemicallyaccepted, and as a result, results in a stable compound.

In addition, the present invention also encompasses N-oxide of thecompound represented by Formula (I) in the scope thereof. Generally, theN-oxide may be formed on any available nitrogen atom. The N-oxide may beformed by an ordinary means, for example, reaction of the compound ofFormula (I) with oxone in the presence of wet alumina.

Next, the aforementioned “pharmaceutically acceptable salt or ester”will be described.

The “salt” of the compound of the present invention meanspharmaceutically acceptable conventional ones. For example, examples ofthereof include base addition salts in a carboxyl group, a hydroxylgroup or an acidic heteroaryl group when the salt has the carboxylgroup, the hydroxyl group or an acidic heteroaryl group such as atetrazolyl group, and acid addition salts in an amino group or a basicheteroaryl group when the salt has the amino group or the basicheteroaryl group.

Examples of the base addition salt include alkali metal salts such as asodium salt and a potassium salt; alkali earth metal salts such as acalcium salt and a magnesium salt; an ammonium salt; organic amine saltssuch as a trimethylamine salt, a triethylamine salt, a dicyclohexylaminesalt, an ethanolamine salt, a diethanolamine salt, a triethanolaminesalt, a procaine salt, an N,N′-dibenzylethylenediamine salt, and thelike.

Examples of the acid addition salt include inorganic acid salts such asa hydrochloric acid salt, a sulfuric acid salt, a nitric acid salt, aphosphoric acid salt, and a perchloric acid salt; organic acid saltssuch as a maleic acid salt, a fumaric acid salt, a tartaric acid salt, acitric acid salt, an ascorbic acid salt, and a trifluoroacetic acidsalt; sulfonic acid salts such as a methane sulfonic acid salt, anisethionic acid salt, a benzene sulfonic acid salt, and a p-toluenesulfonic acid salt and the like.

The “ester” of the compound of the present invention meanspharmaceutically acceptable conventional ones, where a carboxyl group isincluded, for example, in the carboxyl group. Examples of the esterinclude ester with lower alkyl groups, such as a methyl group, an ethylgroup, a propyl group, an isopropyl group, a butyl group, a sec-butylgroup, a tert-butyl group, a pentyl group, an isopentyl group, and aneopentyl group, ester with a cycloalkyl group, such as a cyclopropylgroup, a cyclobutyl group, and a cyclopentyl group, ester with anaralkyl group, such as a benzyl group and a phenethyl group, ester witha lower alkenyl group, such as an allyl group and a 2-butenyl group,ester with lower alkoxy lower alkyl groups, such as a methoxymethylgroup, a 2-methoxyethyl group, and a 2-ethoxyethyl group, ester with alower alkanoyloxy lower alkyl group, such as an acetoxy methyl group, apivaloyloxymethyl group, and a 1-pivaloyloxyethyl group, ester with alower alkoxycarbonyl lower alkyl group, such as a methoxycarbonylmethylgroup and an isopropoxycarbonylmethyl group, ester with a carboxy loweralkyl group, such as a carboxymethyl group, ester with a loweralkoxycarbonyloxy lower alkyl group, such as a1-(ethoxycarbonyloxy)ethyl group, and a 1-(cyclohexyloxycarbonyloxy)ethyl group, ester with a carbamoyloxy lower alkyl group,such as a carbamoyl oxymethyl group, ester with a phthalidyl group,ester with a (5-substituted-2-oxo-1,3-dioxole-4-yl)methyl group, such asa (5-methyl-2-oxo-1,3-dioxole-4-yl)methyl group, and the like.

A method of manufacturing a pharmaceutically acceptable salt of thecompound of the present invention can be performed by appropriatelycombining methods that are ordinarily used in the field of organicsynthesis chemistry. Specifically, examples of the method include amethod of neutralizing and titrating a solution of a free-form compoundof the present invention with an alkali solution or acidic solution, andthe like.

A method of manufacturing the ester of the compound of the presentinvention can be performed by appropriately combining methods that areordinarily used in the field of organic synthesis chemistry.Specifically, the ester of the compound of the present invention can bemanufactured by esterification of a free carboxyl group in accordancewith an ordinary method.

The “pharmaceutically acceptable salt” of the present invention alsoincludes a solvate with a pharmaceutically acceptable solvent such aswater or ethanol.

Next, a method of manufacturing the compound of the present inventionwill be specifically described. However, the present invention is notlimited to these methods of manufacturing. When the compound of thepresent invention is manufactured, the order of the reactions may beappropriately changed. The reaction may be performed from a process orsite that is regarded rational.

In addition, a process of converting a substituent (conversion orfurther modification of the substituent) may be appropriately insertedbetween respective processes. When there is a reactive functional group,protection or de-protection may be appropriately performed. In addition,in order to promote the progress of the reaction, a reagent besides theexemplified reagent may be used appropriately. In heating each reaction,microwave irradiation may be used as necessary. In addition, a rawmaterial compound not described for a method of manufacturing is acommercial compound, or a compound that can be easily prepared bycombination of known synthesis reactions.

The compound obtained in each process can be isolated and purified withan ordinary method conventionally used such as crystallization,re-crystallization, column chromatography, and preparative HPLC, or mayproceed to the next process without isolation and purification as thecase may be.

The “room temperature” in the methods of manufacturing below means 1 to40° C.

Schemes 1 to 8 below are general synthesis methods of the compound ofFormula (I).

Scheme 1: Method of manufacturing compound of Formula (I) from compoundof Formula (II)

The compound of Formula (I) [in the formula, R¹, W¹, W², W³, W⁴, W⁵, X,and Y are as described above, and Z is COOH.] can be obtained byremoving the protective group PG² of the compound represented by Formula(II) [in the formula, R¹, W¹, W², W³, W⁴, W⁵, X, and Y are as describedabove, and PG² is a protective group.].

Herein, the protective group PG² of Formula (II) is not particularlylimited as long as it has the function thereof, but examples thereofinclude a lower alkyl group such as a methyl group, an ethyl group, apropyl group, an isopropyl group, and a tert-butyl group; a halo-loweralkyl group such as a 2,2,2-trichloroethyl group; a lower alkenyl groupsuch as an allyl group; and an aralkyl group such as a benzyl group, ap-methoxybenzyl group, a p-nitrobenzyl group, a benzhydryl group, and atrityl group, particularly preferably, a methyl group, an ethyl group, atert-butyl group, an allyl group, a benzyl group, a p-methoxybenzylgroup, a benzhydryl group, and the like.

A method for removal of the protective group varies depending on thekind of protective group and the stability of the object compound (I)and the like, but is performed by, for example, in accordance with themethod described in the document [see Protective Groups in OrganicSynthesis, 3rd Edition, by T. W. Greene, John Wiley & Sons (1999)] or asimilar method thereto, for example, solvolysis using an acid or base,specifically, for example, a method of reacting 0.01 mole to a largeexcess of an acid, preferably trifluoroacetic acid, formic acid,hydrochloric acid, and the like, or equal mole to a large excess of abase, preferably potassium hydroxide, calcium hydroxide, and the like;chemical reduction using a metal hydride complex and the like; orcatalytic reduction using a palladium-carbon catalyst, a Raney nickelcatalyst, and the like; and the like.

Scheme 2: Method of manufacturing compound of Formula (II) from compoundof Formula (III)

The compound of Formula (II) [in the formula, R¹, W¹, W², W³, W⁴, W⁵, X,and Y are as described above, and PG² is a protective group.] can beobtained by alkylation reaction of the compound represented by Formula(III) [in the formula, W¹, W², W³, W⁴, W⁵, X, and Y are as describedabove, and PG² is a protective group.] and the compound of Formula (IV)[in the formula, R¹ is as described above, and L represents a leavinggroup.].

The leaving group L of Formula (IV) is not particularly limited as longas it produces the compound (II) by elimination by reaction with thecompound (III), and examples of the leaving group include a halogen atom(a chlorine atom, a bromine atom, and the like), a p-toluenesulfonylgroup, a methanesulfonyl group, and the like, and preferably a bromineatom, a chlorine atom, a p-toluenesulfonyl group, and the like.

The amount of the compound (IV) with respect to 1 mole of the usedcompound (III) is ordinarily 1 to 10 mole, and preferably 1 to 3 mole.

Examples of the used base include sodium carbonate, potassium carbonate,a sodium hydrogen carbonate, a sodium hydride, a potassium hydroxide,and the like, and preferably a potassium carbonate, a sodium hydride, apotassium hydroxide, and the like.

The amount of the base is ordinarily 1 to 10 mole, and preferably 1 to 5mole with respect to 1 mole of the compound (III).

The reaction temperature is ordinarily 0° C. to 160° C., and preferably25° C. to 100° C.

The reaction time is ordinarily 1 hour to 24 hours, and preferably 1hour to 12 hours.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asdimethylformamide, N-methyl-2-pyrrolidone, tetrahydrofuran, 1,4-dioxane,acetone, methylethylketone, and acetonitrile.

Scheme 3: Method of manufacturing compound of Formula (III) fromcompound of Formula (V)

The compound of Formula (III) [in the formula, W¹, W², W³, W⁴, W⁵, X,and Y are as described above, and PG² represents a protective group.]can be obtained by removing the protective group PG¹ of the compoundrepresented by Formula (V) [in the formula, W¹, W², W³, W⁴, W⁵, X, and Yare as described above, and PG¹ and PG² represent a protective group.].

Herein, the protective group PG¹ of the above-mentioned Formula (V) isnot particularly limited if it has the function, but examples of thegroup include: an aralkyl group, such as a benzyl group, ap-methoxybenzyl group, a 3,4-dimethoxybenzyl group, an o-nitrobenzylgroup, a p-nitrobenzyl group, a benzhydryl group, and a trityl group; alower alkanoyl group such as a formyl group, an acetyl group, apropionyl group, a butyryl group and a pivaloyl group; a benzoyl group;an aryl alkanoyl group such as a phenylacetyl group and a phenoxyacetylgroup; a lower alkoxycarbonyl group such as a methoxycarbonyl group, anethoxycarbonyl group, a propyloxycarbonyl group, and atert-butoxycarbonyl group; an aralkyloxycarbonyl group such as abenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group and aphenethyloxycarbonyl group; a lower alkyl silyl group such as atrimethylsilyl group and a tert-butyldimethylsilyl group; atetrahydropyranyl group; a trimethylsilylethoxymethyl group; a loweralkylsulfonyl group such as a methylsulfonyl group and an ethylsulfonylgroup; and an arylsulfonyl group such as a benzenesulfonyl group and ap-toluenesulfonyl group, and particularly preferably, atert-butoxycarbonyl group, a methylsulfonyl group, a p-toluenesulfonylgroup and the like.

A method for removal of the protective group varies depending on thekind of protective group and the stability of the object compound (III)and the like, but is performed by, for example, in accordance with themethod described in the document [see Protective Groups in OrganicSynthesis, 3rd Edition, by T. W. Greene, John Wiley & Sons (1999)] or asimilar method thereto, for example, solvolysis using an acid or base,specifically, for example, method of reacting 0.01 mole to a largeexcess of an acid, preferably trifluoroacetic acid, formic acid,hydrochloric acid, and the like; equal mole to a large excess of a base,preferably potassium hydroxide, calcium hydroxide, and the like;chemical reduction using a metal hydride complex, and the like; orcatalytic reduction using a palladium-carbon catalyst, a Raney nickelcatalyst and the like; and the like.

Scheme 4: Method of manufacturing compound of Formula (V) from compoundof Formula (VI)

The compound of Formula (V) [in the formula, W¹, W², W³, W⁴, W⁵, and Yare as described above, and PG¹ and PG² represent a protective group.]can be obtained by esterification of the compound represented by Formula(VI) [in the formula, W¹, W², W³, W⁴, W⁵, X, and Y are as describedabove, and PG¹ represents a protective group.].

Herein, the protective group PG² of Formula (V) is not particularlylimited as long as it has the function thereof, but examples thereofinclude a lower alkyl group such as a methyl group, an ethyl group, apropyl group, an isopropyl group, and a tert-butyl group; a halo-loweralkyl group such as a 2,2,2-trichloroethyl group; a lower alkenyl groupsuch as an allyl group; and an aralkyl group such as a benzyl group, ap-methoxybenzyl group, a p-nitrobenzyl group, a benzhydryl group, and atrityl group, and particularly preferably, a methyl group, an ethylgroup, a tert-butyl group, an allyl group, a benzyl group, ap-methoxybenzyl group, a benzhydryl group, and the like.

A method for introduction of the protective group varies depending onthe kind of protective group and the stability of the compound and thelike, but the protective group can be synthesized, for example, inaccordance with the method described in the document [see ProtectiveGroups in Organic Synthesis, 3rd Edition, by T. W. Greene, John Wiley &Sons (1999)] or a similar method thereto.

Scheme 5: Method of manufacturing compound of Formula (VI) from compoundof Formula (VII)

The compound of Formula (VI) [in the formula, W¹, W², W³, W⁴, W⁵, X, andY are as described above, and PG¹ represents a protective group.] can beobtained by oxidization reaction of the compound represented by Formula(VII) [in the formula, W¹, W², W³, W⁴, W⁵, X, and Y are as describedabove, and PG¹ represents a protective group.]. For example, thecompound of Formula (VI) can be synthesized by reacting sodium chloritein the presence of 2-methyl-2-butene and sodium dihydrogen phosphate ina mixed solvent of tert-butanol-water.

In the reaction, ordinarily 1 to 20 mole, and preferably 1 to 10 mole of2-methyl-2-butene, ordinarily 1 to 5 mole, and preferably 1 to 3 mole ofsodium dihydrogen phosphate, and ordinarily 1 to 10 mole, and preferably1 to 5 mole of sodium chlorite are used with respect to 1 mole of thecompound (VII).

The reaction temperature is ordinarily 0° C. to 100° C., and preferably0° C. to 40° C.

The reaction time is ordinarily 1 hour to 24 hours, and preferably 1hour to for 6 hours.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably water or a mixedsolvent of water and a water-soluble solvent such as tert-butanol oracetonitrile.

Scheme 6: Method of manufacturing compound of Formula (VII) fromcompound of Formula (VIII)

The compound of Formula (VII) [in the formula, W¹, W², W³, W⁴, W⁵, X,and Y are as described above, and PG¹ represents a protective group.]can be obtained by oxidization reaction of the compound represented byFormula (VIII) [in the formula, W¹, W², W³, W⁴, W⁵, X, and Y are asdescribed above, and PG¹ represents a protective group.]. For example,the compound of Formula (VII) can be synthesized by reacting osmiumtetraoxide and sodium periodate in a mixed solvent oftert-butanol-water.

In the reaction, ordinarily 0.0001 to 1 mole, and preferably 0.01 to 1mole of osmium tetraoxide, and ordinarily 1 to 10 mole, and preferably 1to 5 mole of sodium periodate are used with respect to 1 mole of thecompound (VIII).

The reaction temperature is ordinarily 0° C. to 100° C., and preferably0° C. to 40° C.

The reaction time is ordinarily 1 hour to 24 hours, and preferably 1hour to 12 hours.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a mixed solvent ofwater and a water-soluble solvent such as tert-butanol, dioxane oracetone.

Scheme 7: Method of manufacturing compound of Formula (VIII) fromcompound of Formula (IX)

The compound of Formula (VIII) [in the formula, W¹, W², W³, W⁴, W⁵, X,and Y are as described above, and PG¹ represents a protective group.]can be obtained by coupling reaction of the compound represented byFormula (IX) [in the formula, W¹, W², W³, W⁴, and W⁵ are as describedabove, and PG¹ represents a protective group, and X_(L) is a halogenatom.] and Formula (X) [in the formula, X and Y are as described above,and M is boron, tin and the like.]. More specifically, the compound(VIII) can be obtained by reacting the compound (IX) that has a halogenatom and (HO)₂B—X—Y—CH═CH₂ or (n-Bu)₃Sn—X—Y—CH═CH₂ in the presence ofabase and a palladium catalyst (further a phosphine ligand asnecessary).

In the reaction, ordinarily 1 to 10 mole, and preferably 1 to 3 mole ofthe compound (X) is used with respect to 1 mole of the compound (IX).

Examples of the compound (X) include tributylvinyl tin, tributylallyltin and the like.

Examples of the used base include sodium carbonate, potassium carbonate,cesium carbonate, cesium fluoride, potassium fluoride, sodium fluoride,lithium chloride, and the like.

The amount of the used base is ordinarily 1 to 10 mole, and preferably 1to 3 mole with respect to 1 mole of the compound (IX).

Examples of the used palladium catalyst include Pd(PPh₃)₄, Pd(OAc)₂,Pd₂(dba)₃, PdCl₂(PPh₃)₂, and the like.

The amount of the used palladium catalyst is ordinarily 0.01 to 0.5mole, and preferably 0.05 to 0.2 mole with respect to 1 mole of thecompound (IX).

Examples of the used phosphine ligand include PPh₃, P(o-tol)₃,P(tert-Bu)₃, 2-[di(tert-butyl)phosphino]-1,1′-biphenyl,2-[di(tert-butyl)phosphino]-2′-dimethylamino-1,1′-biphenyl,2-[dicyclohexylphosphino]-1,1′-biphenyl,2-[dicyclohexylphosphino]-2′-dimethylamino-1,1′-biphenyl and the like.

The reaction temperature is ordinarily 0° C. to 200° C., and preferably25° C. to 130° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asdimethylformamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, andtoluene.

Scheme 8: Method of manufacturing compound of Formula (IX) from compoundof Formula (XI)

The compound of Formula (IX) [in the formula, W¹, W², W³, W⁴, and W⁵,are as described above, and PG¹ represents a protective group, and X_(L)is a halogen atom.] can be obtained by protecting the compoundrepresented by Formula (XI) [in the formula, W¹, W², W³, W⁴, and W⁵ areas described above, and X_(L) is a halogen atom.] with the protectivegroup PG¹.

The compound (XI) is a commercially available compound or a compoundknown in a document and the like.

Herein, the protective group PG¹ of the above-mentioned Formula (IX) isnot particularly limited as long as it has the function thereof,examples of the group include an aralkyl group such as a benzyl group, ap-methoxybenzyl group, a 3,4-dimethoxybenzyl group, an o-nitrobenzylgroup, a p-nitrobenzyl group, a benzhydryl group, and a trityl group; alower alkanoyl group such as a formyl group, an acetyl group, apropionyl group, a butyryl group, and a pivaloyl group; a benzoyl group;an aryl alkanoyl group, such as a phenylacetyl group and a phenoxyacetylgroup; a lower alkoxycarbonyl group, such as a methoxycarbonyl group, anethoxycarbonyl group, a propyloxy carbonyl group, and atert-butoxycarbonyl group; an aralkyloxy carbonyl group such as abenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, and aphenethyloxycarbonyl group; a lower alkyl silyl group such as atrimethylsilyl group and a tert-butyldimethylsilyl group; atetrahydropyranyl group; a trimethylsilylethoxymethyl group; a loweralkylsulfonyl group, such as a methylsulfonyl group and an ethylsulfonylgroup; an arylsulfonyl group such as a benzenesulfonyl group and ap-toluenesulfonyl group, and in particular, a tert-butoxycarbonyl group,a methylsulfonyl group, a p-toluenesulfonyl group, and the like, arepreferable.

A method for introduction of the protective group varies depending onthe kind of protective group and the stability of the compound and thelike, but the protective group can be synthesized, for example, inaccordance with the method described in the document [see ProtectiveGroups in Organic Synthesis, 3rd Edition, by T. W. Greene, John Wiley &Sons (1999)] or a similar method thereto.

Schemes 9 to 10 below are synthesis methods of the compound of Formula(XV) wherein

is a double bond, and the substituent R^(b) is a halogen atom or thegeneral formula: -Q²-A² in Formula (I).

Scheme 9: Method of manufacturing compound of Formula (XIII) fromcompound of Formula (XII)

The compound of Formula (XIII) [in the formula, R¹, W¹, W³, W⁴, W⁵, andZ are as described above, and X^(b) is a halogen atom.] can be obtainedby halogenation of the compound represented by Formula (XII) [in theformula, R¹, W¹, W³, W⁴, W⁵, X, Y, and Z are as described above.]. Morespecifically, the compound (XIII) can be obtained by reacting thecompound of Formula (XII) and N-chlorosuccinamide or N-bromosuccinamide,and the like.

In the reaction, ordinarily 1 to 10 mole, and preferably 1 to 3 mole ofthe halogenating agent is used with respect to 1 mole of the compound(XII).

Examples of the halogenating agent include N-chlorosuccinamide,N-bromosuccinamide and the like.

The reaction temperature is ordinarily 0° C. to 100° C., and preferably0° C. to 25° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such astetrahydrofuran, 1,4-dioxane, chloroform, and acetonitrile.

Scheme 10: Method of manufacturing compound of Formula (XV) fromcompound of Formula (XIII)

The compound of Formula (XV) [in the formula, R¹, R^(b), W¹, W³, W⁴, W⁵,X, Y, and Z are as described above.] can be obtained by couplingreaction of the compound represented by Formula (XIII) [in the formula,R¹, W¹, W³, W⁴, W⁵, X, Y, and Z are as described above, and X^(b) is ahalogen atom.] and the compound represented by Formula (XIV) [in theformula, R^(b) is an aryl group, a heteroaryl group, a lower alkylgroup, a cyclo-lower alkyl group, a lower alkenyl group, or the like.].More specifically, the compound (XV) can be obtained by reacting thecompound (XIII) that has a halogen atom, and R^(b)—B(OH)₂ and the likein the presence of a base and a palladium catalyst (further a phosphineligand as necessary).

In the reaction, ordinarily 1 to 10 mole, and preferably 1 to 3 mole ofR^(b)—B(OH)₂ is used with respect to 1 mole of the compound (XIII).

As the R^(b)—B(OH)₂, for example, a commercial aryl boron derivative, aheteroaryl boron derivative, a vinyl boron derivative, an allyl boronderivative, a lower alkyl boron derivative, and a cyclo-lower alkylboron derivative such as phenyl boronic acid, phenyl boronic acid ester,and dialkyl phenyl borane may be used. In addition, the intended boronderivative can be manufactured by a known method, a similar methodthereto, or a combination thereof with an ordinary method.

Examples of the used base include sodium carbonate, potassium carbonate,cesium carbonate, cesium fluoride, potassium fluoride, sodium fluoride,and the like.

The amount of the used base is ordinarily 1 to 10 mole, and preferably 1to 3 mole with respect to 1 mole of the compound (XIII).

Examples of the used palladium catalyst include Pd(PPh₃)₄, Pd(OAc)₂, Pd₂(dba)₃, PdCl₂(PPh₃)₂, and the like.

The amount of the used palladium catalyst is ordinarily 0.01 to 0.5mole, and preferably 0.05 to 0.2 mole with respect to 1 mole of thecompound (XIII).

Examples of the used phosphine ligand include PPh₃, P(o-tol)₃,P(tert-Bu)₃, 2-[di(tert-butyl)phosphino]-1,1′-biphenyl,2-[di(tert-butyl)phosphino]-2′-dimethylamino-1,1′-biphenyl,2-[dicyclohexylphosphino]-1,1′-biphenyl,2-[dicyclohexylphosphino]-2′-dimethylamino-1,1′-biphenyl and the like.

The reaction temperature is ordinarily 0° C. to 200° C., and preferably25° C. to 130° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asdimethylformamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, andtoluene.

Schemes 11 to 16 below are other synthesis methods of the compoundrepresented by Formula (III-I) wherein X is a single bond and Y is amethylene group in the compound of Formula (III).

Scheme 11: Method of manufacturing compound of Formula (III-1) fromcompound of Formula (XVI)

The compound of Formula (III-1) [in the formula, W¹, W², W³, W⁴, and W⁵are as described above, and PG² represents a protective group.] can beobtained by esterification of the compound represented by Formula (XVI)[in the formula, W¹, W², W³, W⁴ and W⁵ are as described above.].

Herein, the protective group PG² of the above-mentioned Formula (III-1)is not particularly limited as long as it has the function thereof, butexamples of the group include: a lower alkyl group such as a methylgroup, an ethyl group, a propyl group, an isopropyl group and atert-butyl group; a halo-lower alkyl group such as a2,2,2-trichloroethyl group; a lower alkenyl group such as an allylgroup; and an aralkyl group such as a benzyl group, a p-methoxybenzylgroup, a p-nitrobenzyl group, a benzhydryl group, and a trityl group,and the like, and particularly preferably, a methyl group, an ethylgroup, a tert-butyl group, an allyl group, a benzyl group,p-methoxybenzyl group, and a benzhydryl group, and the like.

A method for introduction of the protective group varies depending onthe kind of protective group and the stability of the compound and thelike, but the protective group can be synthesized, for example, inaccordance with the method described in the document [see ProtectiveGroups in Organic Synthesis, 3rd Edition, by T. W. Greene, John Wiley &Sons (1999)] or a similar method thereto.

Scheme 12: Method of manufacturing compound of Formula (XVI) fromcompound of Formula (XVII)

The compound of Formula (XVI) [in the formula, W¹, W², W³, W⁴, and W⁵are as described above.] can be obtained by hydrolysis of the compoundrepresented by Formula (XVII) [in the formula, W¹, W², W³, W⁴, and W⁵are as described above, and PG¹ is a protective group.]. Morespecifically, the compound of Formula (XVI) can be obtained byde-protection of the protective group PG¹ along with hydrolysis of thecyano group of the compound of Formula (XVII).

Herein, the protective group PG¹ of a compound denoted by theabove-mentioned Formula (XVII) is not particularly limited as long as ithas the function thereof, but examples of the group include: a loweralkanoyl group such as a formyl group, an acetyl group, a propionylgroup, a butyryl group, and a pivaloyl group; a benzoyl group; an arylalkanoyl group such as a phenylacetyl group, phenoxyacetyl group; alower alkoxycarbonyl group such as a methoxycarbonyl group, anethoxycarbonyl group, a propyloxycarbonyl group, and atert-butoxycarbonyl group; an aralkyloxycarbonyl group such as abenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, and aphenethyl oxycarbonyl group; a lower alkylsilyl group such as atrimethylsilyl group and a tert-butyldimethylsilyl group; a loweralkylsulfonyl group such as a methylsulfonyl group and an ethyl sulfonylgroup; and an arylsulfonyl group such as a benzenesulfonyl group and ap-toluenesulfonyl group, and the like, and particularly preferably, atert-butoxycarbonyl group, a methylsulfonyl group, and ap-toluenesulfonyl group and the like.

This hydrolysis reaction is performed by using acid or base hydrolysis,specifically, for example, a method of reacting 0.01 mole to a largeexcess of an acid, preferably acetic acid, formic acid, sulfuric acid,phthalic acid, hydrochloric acid and the like, or 0.01 mole to a largeexcess of a base, preferably sodium hydroxide, potassium hydroxide andthe like.

The reaction temperature is ordinarily 0° C. to 200° C., and preferably0° C. to 160° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asmethanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,tert-butanol, tetrahydrofuran, 1,4-dioxane, cyclohexane,1,3-dimethylbenzene, and toluene.

Scheme 13: Method of manufacturing compound of Formula (XVII) fromcompound of Formula (XVIII)

The compound of Formula (XVII) [in the formula, W¹, W², W³, W⁴ and W⁵are as described above, and PG¹ is a protective group.] can be obtainedby cyanation of the compound represented by Formula (XVIII) [in theformula, W¹, W², W³, W⁴ and W⁵ are as described above, and PG¹ is aprotective group, and L is a leaving group.].

The leaving group L of Formula (XVIII) is not particularly limited aslong as it has the function thereof, but examples thereof include ahalogen atom (a chlorine atom, a bromine atom, and the like), ap-toluenesulfonyloxy group, a benzenesulfonyloxy group, amethanesulfonyloxy group, ethanesulfonyloxy, and the like, andpreferably a bromine atom, a chlorine atom, a p-toluenesulfonyloxygroup, a methanesulfonyloxy group, and the like.

In the reaction, ordinarily 1 mole to 10 mole, and preferably 1 mole to3 mole of the cyanide is used with respect to 1 mole of the compound(XVIII).

Examples of the used cyanide include lithium cyanide, sodium cyanide,potassium cyanide, tetraethyl cyanide, trimethylsilyl cyanide,tetrabutyl cyanide, and the like.

The reaction temperature is ordinarily 0° C. to 200° C., and preferably0° C. to 160° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asN,N-dimethylformamide, N,N-dimethylacetoamide, dimethylsulfoxide,methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,tert-butanol, tetrahydrofuran, dimethoxyethane, 1,4-dioxane,cyclohexane, 1,3-dimethylbenzene, and toluene.

Scheme 14: Method of manufacturing compound of Formula (XVIII) fromcompound of Formula (XIX)

The compound of Formula (XVIII) [in the formula, W¹, W², W³, W⁴ and W⁵are as described above, and PG¹ is a protective group, and L is aleaving group.] can be obtained by conversion of the hydroxyl group ofthe compound represented by Formula (XIX) [in the formula, W¹, W², W³,W⁴, and W⁵ are as described above, and PG¹ is a protective group.] to aleaving group such as a chlorine atom, a bromine atom, an iodine atom, amethanesulfonyloxy group, and a p-toluenesulfonyloxy group in thepresence of a base.

The leaving group L of Formula (XVIII) is not particularly limited aslong as it has the function thereof, but examples thereof include ahalogen atom (a chlorine atom, a bromine atom and the like), ap-toluenesulfonyloxy group, a benzenesulfonyloxy group, amethanesulfonyloxy group, ethanesulfonyloxy, and the like, andpreferably a bromine atom, a chlorine atom, a p-toluenesulfonyloxygroup, a methanesulfonyloxy group, and the like.

In the reaction, as the compound leading to a leaving group, forexample, ordinarily 1 mole to 10 mole, and preferably 1 mole to 3 moleof sulfonic acid chloride is used with respect to 1 mole of the compound(XIX).

Examples of the used sulfonic acid chloride include methane sulfonylchloride, ethanesulfonyl chloride, p-toluene sulfonyl chloride,phenylsulfonyl chloride, and the like.

Examples of the used base include triethylamine, diisopropylethylamine,and the like.

The reaction temperature is ordinarily 0° C. to 200° C., and preferably0° C. to 25° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such aschloroform, dichloromethane, tetrahydrofuran, dimethoxyethane,1,4-dioxane, cyclohexane, 1,3-dimethyl benzene, and toluene.

In addition, the compound of Formula (XVIII) can be also obtained byAppel reaction in which the compound represented by Formula (XIX) isreacted with a halogenating agent such as carbon tetrabromide and carbontetrachloride, and triphenyl phosphine.

In the reaction, ordinarily 1 mole to 10 mole, and preferably 1 mole to3 mole of the halogenating agent is used with respect to 1 mole of thecompound (XIX).

Examples of the used halogenating agent include carbon tetrabromide,carbon tetrachloride, hexachloroacetone, hexabromoacetone, triphosgene,lithium bromide, methane iodide, bromine, iodine, and the like.

In the reaction, ordinarily 1 mole to 10 mole, and preferably 1 mole to3 mole of triphenylphosphine is used with respect to 1 mole of thecompound (XIX).

The reaction temperature is ordinarily 0° C. to 200° C., and preferably0° C. to 25° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such aschloroform, dichloromethane, tetrahydrofuran, dimethoxyethane,1,4-dioxane, cyclohexane, 1,3-dimethylbenzene, acetonitrile, andtoluene.

Scheme 15: Method of manufacturing compound of Formula (XIX) fromcompound of Formula (XX)

The compound of Formula (XIX) [in the formula, W¹, W², W³, W⁴ and W⁵ areas described above, and PG¹ is a protective group.] can be obtained byreduction of the compound represented by Formula (XX) [in the formula,W¹, W², W³, W⁴ and W⁵ are as described above, and PG¹ and PG² areprotective groups.]. More specifically, the compound of Formula (XIX)can be obtained by reacting the compound of Formula (XX) that has anester, with a reducing agent such as lithium aluminum hydride.

Herein, the protective group PG² of the above-mentioned Formula (XX) isnot particularly limited as long as it has the function thereof, butexamples of the group include: a lower alkyl group such as a methylgroup, an ethyl group, a propyl group, an isopropyl group, and atert-butyl group; a halo-lower alkyl group, such as 2,2,2-trichloroethylgroup; a lower alkenyl group, such as an allyl group; an aralkyl groupsuch as a benzyl group, a p-methoxybenzyl group, a p-nitrobenzyl group,a benzhydryl group, and a trityl group, and the like, and particularlypreferably, a methyl group, an ethyl group, a tert-butyl group, an allylgroup, a benzyl group, a p-methoxybenzyl group, and a benzhydryl group.

In the reaction, ordinarily 1 mole to 10 mole, and preferably 1 mole to3 mole of the reducing agent is used with respect to 1 mole of thecompound (XX).

Examples of the used reducing agent include lithium aluminum hydride,diisobutylaluminum hydride, triethyl boron lithium hydride,bis(2-methoxyethoxy)aluminum sodium hydride, boron hydride, and thelike.

The reaction temperature is ordinarily −100° C. to 200° C., andpreferably 0° C. to 25° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asdiethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane,cyclohexane, 1,3-dimethylbenzene, toluene, methanol, ethanol,1-propanol, and 2-propanol.

Scheme 16: Method of manufacturing compound of Formula (XX) fromcompound of Formula (XXI)

The compound of Formula (XX) [in the formula, W¹, W², W³, W⁴ and W⁵ areas described above, and PG¹ and PG² are protective groups.] can beobtained by protecting the compound represented by Formula (XXI) [in theformula, W¹, W², W³, W⁴ and W⁵ are as described above, and PG² is aprotective group.] with the protective group PG¹.

Herein, the protective group PG¹ of the above-mentioned Formula (XX) isnot particularly limited as long as it has the function thereof, butexamples of the group includes: an aralkyl group such as a benzyl group,a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group, an o-nitrobenzylgroup, a p-nitrobenzyl group, a benzhydryl group, and a trityl group; alower alkanoyl group such as a formyl group, an acetyl group, apropionyl group, a butyryl group and a pivaloyl group; a benzoyl group;an aryl alkanoyl group such as a phenylacetyl group, and a phenoxyacetylgroup; a lower alkoxycarbonyl group, such as a methoxycarbonyl group, anethoxycarbonyl group, a propyloxycarbonyl group, and atert-butoxycarbonyl group; an aralkyloxy carbonyl group such as abenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, and aphenethyloxycarbonyl group; a lower alkyl silyl group, such as atrimethylsilyl group and a tert-butyldimethylsilyl group;tetrahydropyranyl group; a trimethylsilylethoxymethyl group; a loweralkylsulfonyl group, such as a methylsulfonyl group and an ethylsulfonyl group; and an arylsulfonyl group such as a benzenesulfonylgroup and a p-toluenesulfonyl group, and the like, and particularlypreferably, a tert-butoxycarbonyl group, a methylsulfonyl group, and ap-toluenesulfonyl group and the like.

A method for introduction of the protective group varies depending onthe kind of protective group and the stability of the compound and thelike, but the protective group can be synthesized, for example, inaccordance with the method described in the document [see ProtectiveGroups in Organic Synthesis, 3rd Edition, by T. W. Greene, John Wiley &Sons (1999)] or a similar method thereto.

Meanwhile, examples of the compound of Formula (XXI) include, forexample, methyl lindole-6-carboxylate, ethyl indole-6-carboxylate,benzyl indole-6-carboxylate, tert-butyl indole-6-carboxylate, methyl3-methyl-1H-lindole-6-carboxylate, ethyl3-methyl-1H-indole-6-carboxylate, methyl3-ethyl-1H-indole-6-carboxylate, methyl3-isopropyl-1H-indole-6-carboxylate, methyl1H-pyrrolo[3,2-b]pyridin-6-carboxylate, methyl lindazole-6-carboxylate,ethyl indazole-6-carboxylate, methyl 3-methylindazole-6-carboxylate, andthe like. The compound of Formula (XXI) may use a commercial product, ormay be manufactured by appropriately combining known methods or themethods described in Examples, or a similar method thereto as necessary.

Schemes 17 to 18 below are other synthesis methods of the compoundrepresented by Formula (II-1) wherein the group represented by X is asingle bond, and the group represented by Y is an a group represented byCR^(Y1)R^(Y1′) in the compound represented by Formula (II).

Scheme 17: Method of manufacturing compound of Formula (II-1) fromcompound of Formula (XXII)

The compound of Formula (II-1) [in the formula, R¹, R^(Y1), R^(Y1′), W¹,W², W³, W⁴, and W⁵ are as described above, and PG² represents aprotective group.] can be obtained by coupling reaction of the compoundrepresented by Formula (XXII) [in the formula, R¹, W¹, W², W³, W⁴ and W⁵are as described above, and X_(L) is a halogen atom.] and Formula(XXIII) [in the formula, R^(Y1), R^(Y1′) are as described above, and PG²represents a protective group.]. More specifically, the compound (II-1)can be obtained by reacting the compound (XXII) that has a halogen atomwith the compound (XXIII), in the presence of a base and a palladiumcatalyst (further a phosphine ligand as necessary).

In the reaction, ordinarily 1 to 10 mole, and preferably 1 to 3 mole ofthe compound (XXIII) is used with respect to 1 mole of the compound(XXII).

Examples of the compound (XXIII) include methyl acetate, ethyl acetate,tert-butyl acetate, methyl propionate, ethyl propionate, tert-butylpropionate, methyl isobutyrate, and the like.

Examples of the used base include lithium dicyclohexylamide, sodiumdicyclohexylamide, lithium hexamethyldisilazide, sodiumhexamethyldisilazide, potassium hexamethyldisilazide, lithiumdiisopropylamide, and the like.

The amount of the used base is ordinarily 1 to 10 mole, and preferably 1to 3 mole with respect to 1 mole of the compound (XXII).

Examples of the used palladium catalyst include Pd(PPh₃)₄, Pd(OAc)₂,Pd(dba)₂, Pd₂(dba)₃, PdCl₂(PPh₃)₂, and the like.

The amount of the used palladium catalyst is ordinarily 0.01 to 0.5mole, and preferably 0.05 to 0.2 mole with respect to 1 mole of thecompound (XXII).

Examples of the used phosphine ligand include PPh₃, P(o-tol)₃,P(tert-Bu)₃, 2-[di(tert-butyl)phosphino]-1,1′-biphenyl,2-[di(tert-butyl)phosphino]-2′-dimethylamino-1,1′-biphenyl,1,2,3,4,5-pentaphenyl-1′-[di(tert-butyl)phosphino]ferrocene,2-[dicyclohexylphosphino]-1,1′-biphenyl,2-[dicyclohexylphosphino]-2′-dimethylamino-1,1′-biphenyl, and the like.

The reaction temperature is ordinarily 0° C. to 80° C., and preferably0° C. to 25° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asN,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, cyclohexane,1,3-dimethylbenzene, acetonitrile, and toluene.

Scheme 18: Method of manufacturing compound of Formula (XXII) fromFormula (XXIV)

The compound of Formula (XXII) [in the formula, R¹, W¹, W², W³, W⁴ andW⁵ are as described above, and X_(L) is a halogen atom.] can be obtainedby alkylation reaction of the compound represented by Formula (XXIV) [inthe formula, W¹, W², W³, W⁴ and W⁵ are as described above, and X_(L) isa halogen atom.] and the compound of Formula (IV) [in the formula, R¹ isas described above, and L represents a leaving group.] in the presenceof a base.

The leaving group L of Formula (IV) is not particularly limited as longas it is eliminated by the reaction with the compound (IV) to producethe compound (XXII), and examples of the leaving group include a halogenatom (a chlorine atom, a bromine atom, and the like), ap-toluenesulfonyloxy group, a benzenesulfonyloxy group, anethanesulfonyloxy group, a methanesulfonyloxy group, and the like, andpreferably a bromine atom, a chlorine atom, a p-toluenesulfonyloxygroup, and the like.

The amount of the used compound (IV) is ordinarily 1 to 10 mole, andpreferably 1 to 3 mole with respect to 1 mole of the compound (XXIV).

Examples of the used base include sodium carbonate, potassium carbonate,cesium carbonate, sodium hydrogen carbonate, cesium fluoride, sodiumhydride, potassium hydroxide, and the like, and preferably potassiumcarbonate, sodium hydride, potassium hydroxide, and the like.

The amount of the base is ordinarily 1 to 10 mole, and preferably 1 to 5mole with respect to 1 mole of the compound (XXIV).

The reaction temperature is ordinarily 0° C. to 160° C., and preferably25° C. to 100° C.

The reaction time is ordinarily 1 hour to 24 hours, and preferably 1hour to 12 hours.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asN,N-dimethylformamide, N,N-dimethylacetoamide, N-methyl-2-pyrrolidone,chloroform, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone,methylethylketone, and acetonitrile.

Examples of the compound of Formula (XXIV) include 6-bromoindole,6-bromo-3-methylindole, 6-bromo-3-ethylindole, 6-bromoindazole,6-bromo-2,3-dihydro-1H-indole,6-bromo-2,3-dihydro-3-methyl-1H-indole-2-one,6-bromo-2,3-dihydro-3-methyl-1H-indole,6-bromo-2,3-dihydro-3,3-dimethyl-1H-indole-2-one,6-bromo-2,3-dihydro-3,3-dimethyl-1H-indole,6-bromo-3-methyl-1H-indazole, 6-bromo-3-ethyl-1H-indazole,6-bromo-3-propyl-1H-indazole, 6-bromo-3-isopropyl-1H-indazole,6-bromo-3-cyclopropyl-1H-indazole, 6-bromo-1H-indazole-3-carbonitrile,6-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine,6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine,6-bromo-3-ethyl-1H-pyrazolo[4,3-b]pyridine,6-bromo-3-propyl-1H-pyrazolo[4,3-b]pyridine,6-bromo-3-cyclopropyl-1H-pyrazolo[4,3-b]pyridine,6-bromo-3-chloro-1H-pyrazolo[4,3-b]pyridine, and6-chloro-5-methoxy-3-methyl-1H-indazole and the like. The compound ofFormula (XXIV) may use a commercial product, or can be manufactured by asuitable combination of known methods or the methods described inExample or a similar method thereto as necessary.

Scheme 19 to 20 below are synthesis methods of the compound representedby Formula (III-2) wherein the group represented by X is a single bond,and the group represented by Y is —(CH₂)₂—(CH₂)_(m)— (herein m is anyinteger of 0 to 4) in the compound represented by Formula (III).

Scheme 19: Method of manufacturing compound of Formula (III-2) fromcompound of Formula (III-3)

The compound of Formula (III-2) [in the formula, W¹, W², W³, W⁴, and W⁵are as described above, m is any integer of 0 to 4, and PG² represents aprotective group.] can be obtained by reduction reaction of the compoundrepresented by Formula (III-3) [in the formula, W¹, W², W³, W⁴ and W⁵are as described above, m is any integer of 0 to 4, and PG² represents aprotective group.]. More specifically, the compound (III-2) can beobtained by reacting the compound (III-3) that has an alkene group inthe presence of a reduction catalyst such as palladium on carbon underhydrogen atmosphere.

Examples of the used catalyst include 5% palladium on carbon, 10%palladium on carbon, 20% palladium hydroxide, R any nickel, platinum,platinum oxide, and the like.

The amount of the used catalyst is ordinarily 0.01 to 1 mole, andpreferably 0.05 to 0.2 mole with respect to 1 mole of the compound(III-3).

The reaction temperature is ordinarily 0° C. to 200° C., and preferably25° C. to 80° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asmethanol, ethanol, 1-propanol, 2-propanol, ethyl acetate,dimethylformamide, dimethylacetoamide, tetrahydrofuran, 1,4-dioxane, andtoluene.

Scheme 20: Method of manufacturing compound of Formula (III-3) fromcompound of Formula (XXIV)

The compound of Formula (III-3) [in the formula, W¹, W², W³, W⁴ and W⁵are as described above, m is any integer of 0 to 4, and PG² represents aprotective group.] can be obtained by coupling reaction of the compoundrepresented by Formula (XXIV) [in the formula, W¹, W², W³, W⁴, and W⁵are as described above, and X_(L) is a halogen atom.] and Formula (XXV)[in the formula, m is any integer of 0 to 4, and PG² represents aprotective group.]. More specifically, the compound (III-3) can beobtained by reacting the compound (XXIV) that has a halogen atom withthe compound (XXV) in the presence of abase and a palladium catalyst(further a phosphine ligand as necessary).

In the reaction, ordinarily 1 to 10 mole, and preferably 1 to 3 mole ofthe compound (XXV) is used with respect to 1 mole of the compound(XXIV).

Examples of the compound (XXV) include methyl acrylate, ethyl acrylate,propyl acrylate, tert-butyl acrylate, methyl 2-butenoate, methyl3-butenoate, acrylic acid, 2-butenoic acid, 3-butenoic acid, and thelike.

Examples of the used base include triethyl amine, sodium acetate,potassium acetate, sodium hydrogen carbonate, sodium carbonate, cesiumfluoride, potassium fluoride, potassium carbonate, and the like.

The amount of the used base is ordinarily 1 to 10 mole, and preferably 1to 3 mole with respect to 1 mole of the compound (XXIV).

Examples of the used palladium catalyst include Pd(PPh₃)₄, Pd(OAc)₂,Pd₂(dba)₃, PdCl₂(PPh₃)₂, and the like.

The amount of the used palladium catalyst is ordinarily 0.01 to 0.5mole, and preferably 0.05 to 0.2 mole with respect to 1 mole of thecompound (XXIV).

Examples of the used phosphine ligand include PPh₃, P(o-tol)₃,P(2-furyl)₃, P(tert-Bu)₃, 2-[di(tert-butyl)phosphino]-1,1′-biphenyl,2-[di(tert-butyl)phosphino]-2′-dimethylamino-1,1′-biphenyl,2-[dicyclohexylphosphino]-1,1′-biphenyl,2-[dicyclohexylphosphino]-2′-dimethylamino-1,1′-biphenyl, and the like.

The reaction temperature is ordinarily 0° C. to 200° C., and preferably25° C. to 160° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asN,N-dimethylformamide, N,N-dimethylacetoamide, chloroform,dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, andtoluene.

Examples of a compound of Formula (XXIV), include 6-bromoindole,6-bromo-3-methylindole, 6-bromo-3-ethylindole, 6-bromoindazole,6-bromo-2,3-dihydro-1H-indole,6-bromo-2,3-dihydro-3-methyl-1H-indole-2-one,6-bromo-2,3-dihydro-3-methyl-1H-indole,6-bromo-2,3-dihydro-3,3-dimethyl-1H-indole-2-one,6-bromo-2,3-dihydro-3,3-dimethyl-1H-indole,6-bromo-3-methyl-1H-indazole, 6-bromo-3-ethyl-1H-indazole,6-bromo-3-propyl-1H-indazole, 6-bromo-3-isopropyl-1H-indazole,6-bromo-3-cyclo propyl-1H-indazole, 6-bromo-1H-indazole-3-carbonitrile,6-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine,6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine,6-bromo-3-ethyl-1H-pyrazolo[4,3-b]pyridine,6-bromo-3-propyl-1H-pyrazolo[4,3-b]pyridine,6-bromo-3-cyclopropyl-1H-pyrazolo[4,3-b]pyridine,6-bromo-3-chloro-1H-pyrazolo[4,3-b]pyridine,6-chloro-5-methoxy-3-methyl-1H-indazole, and the like. The compound ofFormula (XXIV) may use a commercial product, or can be manufactured by asuitable combination of known methods or the methods described inExample or a similar method thereto as necessary.

Schemes 21 to 23 are synthesis methods of the compound represented byFormula (I-1) wherein Z is a 5-tetrazolyl group in the compound ofFormula (I).

Scheme 21: Method of manufacturing compound of Formula (I-1) fromcompound of Formula (XXVI)

The compound of Formula (I-1) [in the formula, R¹, W¹, W², W³, W⁴, W⁵,X, and Y are as described above.] can be obtained by the reaction of thecompound represented by Formula (XXVI) [in the formula, R¹, W¹, W², W³,W⁴, W⁵, X, and Y are as described above.] and azide. More specifically,the compound (I-1) can be obtained by reacting the compound (XXVI) thathas a cyano group with an azide such as sodium azide, in the presence ofa salt such as ammonium chloride.

In the reaction, ordinarily 1 to 10 mole, and preferably 1 to 3 mole ofthe azide is used with respect to 1 mole of the compound (XXVI).

Examples of the azide include alkali metal azides such as lithium azide,sodium azide, and potassium azide, trialkyl tin azides such as trioctyltin azide or hydrazoic acid and the like.

Examples of the used salt include ammonium chloride, zinc chloride, zincbromide, aluminum chloride, and the like.

The amount of the used salt is ordinarily 1 to 10 mole, and preferably 1to 3 mole with respect to 1 mole of the compound (XXVI).

The reaction temperature is ordinarily 0° C. to 200° C., and preferably100° C. to 170° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asdimethylformamide, water, dimethylacetoamide, N-methyl-2-pyrrolidone,tetrahydrofuran, 1,4-dioxane, and toluene.

Scheme 22: Method of manufacturing compound of Formula (XXVI) fromcompound of Formula (XXVII)

The compound of Formula (XXVI) [in the formula, R¹, W¹, W², W³, W⁴, W⁵,X, and Y are as described above.] can be obtained by dehydrationreaction of the compound represented by Formula (XXVII) [in the formula,R¹, W¹, W², W³, W⁴, W⁵, X, and Y are as described above.]. Morespecifically, the compound (XXVI) can be obtained by reacting thecompound (XXVII) that has an amide group in the presence of adehydrating agent such as thionyl chloride.

In the reaction, ordinarily 1 to 10 mole, and preferably 1 to 3 mole ofthe dehydrating agent is used with respect to 1 mole of the compound(XXVII).

Examples of the dehydrating agent include thionyl chloride, oxalylchloride, cyanuric acid chloride, phosphorus pentaoxide, phosphoruspentachloride, acetic anhydride, phosphorus oxychloride, and the like.

The reaction temperature is ordinarily 0° C. to 200° C., and preferably0° C. to 25° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asdichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile,and toluene.

Scheme 23: Method of manufacturing compound of Formula (XXVII) fromcompound of Formula (I) (in the formula, Z is COOH)

The compound of Formula (XXVII) [in the formula, R¹, W¹, W², W³, W⁴, W⁵,X, and Y are as described above.] can be obtained by amidation reactionof the compound represented by Formula (I) [in the formula, R¹, W¹, W²,W³, W⁴, W⁵, X, and Y are as described above.]. More specifically, thecompound (XXVII) that has an amide group can be obtained by reacting thecompound represented by Formula (I) with a halogenating agent such asthionyl chloride and oxalyl chloride, whereby to produce correspondingacid chloride, and reacting the acid chloride with ammonia water.

In the reaction, ordinarily 1 to 10 mole, and preferably 1 to 3 mole ofthe halogenating agent is used with respect to 1 mole of the compound(I).

Examples of the halogenating agent include thionyl chloride, oxalylchloride, phosphorus trichloride, phosphorus pentachloride, sulfurylchloride, and the like.

The reaction temperature is ordinarily 0° C. to 200° C., and preferably0° C. to 25° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asdichloromethane, chloroform, tetrahydrofuran, 1,3-dimethylbenzene,1,4-dioxane, and toluene.

Scheme 24 below is a synthesis method of the compound represented byFormula (XXVI-1) wherein X is a single bond and Y is a single bond inthe compound of Formula (XXVI).

Scheme 24: Method of manufacturing compound of Formula (XXVI-1) fromcompound of Formula (XXII)

The compound of Formula (XXVI-1) [in the formula, R¹ is as describedabove, and W¹, W², W³, W⁴, and W⁵ are as described above.] can beobtained by coupling reaction of the compound represented by Formula(XXII) [in the formula, R¹ is as described above, and W¹, W², W³, W⁴,and W⁵ are as described above, and X_(L) is a halogen atom.] and acyanide such as zinc cyanide. More specifically, the compound (XXVI-1)can be obtained by reacting the compound (XXII) that has a halogen atomwith a cyanide in the presence of a palladium catalyst (further aphosphine ligand as necessary).

In the reaction, ordinarily 1 to 10 mole, and preferably 1 to 3 mole ofthe cyanide is used with respect to 1 mole of the compound (XXII).

Examples of the cyanide include zinc cyanide, sodium cyanide, potassiumcyanide, and the like.

Examples of the used palladium catalyst include Pd(PPh₃)₄, Pd(OAc)₂,Pd(dba)₂, Pd₂(dba)₃, PdCl₂(PPh₃)₂, and the like.

The amount of the used palladium catalyst is ordinarily 0.01 to 0.5mole, and preferably 0.05 to 0.2 mole with respect to 1 mole of thecompound (XXII).

Examples of the used phosphine ligand include PPh₃, P(o-tol)₃,P(tert-Bu)₃, 2-[di(tert-butyl)phosphino]-1,1′-biphenyl,2-[di(tert-butyl)phosphino]-2′-dimethylamino-1,1′-biphenyl,2-[dicyclohexylphosphino]-1,1′-biphenyl,2-[dicyclohexylphosphino]-2′-dimethylamino-1,1′-biphenyl, and the like.

A reducing agent such as zinc may be added as necessary in thisreaction.

The reaction temperature is ordinarily 0° C. to 200° C., and preferably25° C. to 130° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asdimethylformamide, tetrahydrofuran, dimethoxyethane, 1,4-dioxane,acetonitrile, and toluene.

Scheme 25 below is another synthesis method of the compound of Formula(I).

Scheme 25: Method of manufacturing of compound of Formula (I) fromFormula (XXVI)

The compound of Formula (I) [in the formula, R¹, W¹, W², W³, W⁴, W⁵, X,and Y are as described above, and Z is COOH.] can be obtained byhydrolysis reaction of the compound represented by Formula (XXVI) [inthe formula, R¹, W¹, W², W³, W⁴, W⁵, X, and Y are as described above.].More specifically, the compound (I) can be obtained by solvolysis usingan acid or a base, specifically, for example, a method of reacting 0.01mole to a large excess of an acid, preferably acetic acid, hydrochloricacid, sulfuric acid, trifluoroacetic acid, phthalic acid and the like,or 0.01 mole to a large excess of a base, preferably potassiumhydroxide, sodium hydroxide, calcium hydroxide and the like in thepresence of an alcoholic solvent.

The reaction temperature is ordinarily 0° C. to 200° C., and preferably0° C. to 160° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asmethanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,tert-butanol, tetrahydrofuran, 1,4-dioxane, cyclohexane,1,3-dimethylbenzene, and toluene.

The alcoholic solvent used in the solvolysis using the base is notparticularly limited as long as it has no adverse effect on thereaction, but is preferably methanol, ethanol, 1-propanol, 2-propanol,1-butanol, 2-butanol, tert-butanol, and the like.

Scheme 26 below is a general method of manufacturing the compound ofFormula (II-2) wherein X is a carbonyl group in the compound of Formula(II).

Scheme 26: Method of manufacturing compound of Formula (II-2) fromFormula (XXVIII)

The compound of Formula (II-2) [in the formula, R¹, W¹, W², W³, W⁴, W⁵,and Y are as described above, and PG² represents a protective group.]can be obtained by coupling reaction of the compound represented byFormula (XXVIII) [in the formula, R¹, W¹, W², W³, W⁴, and W⁵ are asdescribed above, and M is boron, tin, and the like.] and an acidchloride. More specifically, the compound (II-2) can be obtained byreacting the compound (XXVIII) with an acid chloride in the presence ofa palladium catalyst (further a phosphine ligand as necessary and abase).

In the reaction, ordinarily 1 to 10 mole, and preferably 1 to 3 mole ofthe acid chloride is used with respect to 1 mole of the compound(XXVIII).

Examples of the acid chloride include methyl 3-chlorocarbonylpropionateethyl 3-chlorocarbonylpropionate, ethyl chloroglyoxylate, and the like.

PG² in Formula (II-2) is a group derived from the acid chloride, andexamples thereof include a methyl group, an ethyl group, and the like.

Examples of the used base include triethyl amine, diisopropylethylamine, and the like.

The amount of the used base is ordinarily 1 to 10 mole, and preferably 1to 3 mole with respect to 1 mole of the compound (XXVIII).

Examples of the used palladium catalyst include Pd(PPh₃)₄, Pd(OAc)₂,Pd(dba)₂, Pd₂(dba)₃, PdCl₂(PPh₃)₂, and the like.

The amount of the used palladium catalyst is ordinarily 0.01 to 0.5mole, and preferably 0.05 to 0.2 mole with respect to 1 mole of thecompound (XXVIII).

Examples of the used phosphine ligand include PPh₃, P(o-tol)₃,P(tert-Bu)₃, 2-[di(tert-butyl)phosphino]-1,1′-biphenyl,2-[di(tert-butyl)phosphino]-2′-dimethylamino-1,1′-biphenyl,2-[dicyclohexylphosphino]-1,1′-biphenyl,2-[dicyclohexylphosphino]-2′-dimethylamino-1,1′-biphenyl, and the like.

The reaction temperature is ordinarily 0° C. to 200° C., and preferably25° C. to 130° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asdimethylformamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, andtoluene.

Scheme 27: Method of manufacturing compound of Formula (XXVIII) fromFormula (XXII)

The compound of Formula (XXVIII) [in the formula, R¹, W¹, W², W³, W⁴,and W⁵ are as described above, and M is boron, tin, and the like.] canbe obtained by coupling reaction of the compound represented by Formula(XXII) [in the formula, R¹, W¹, W², W³, W⁴, and W⁵ are as describedabove, and X_(L) is a halogen atom.] and Formula (XXIX) [in the formula,M is boron, tin, and the like.]. More specifically, the compound(XXVIII) can be obtained by reacting the compound (XXII) that has ahalogen atom with the compound (XXIX) in the presence of a palladiumcatalyst (further a phosphine ligand as necessary and a base).

In the reaction, the ordinarily 1 to 10 mole, and preferably 1 to 3 moleof the compound (XXIX) is used with respect to 1 mole of the compound(XXII).

Examples of the compound (XXIX) include bis(trimethyl tin), bis(triethyltin), bis(tributyl tin), bis(pinacolato)diboron, and the like.

Examples of the used base include potassium acetate, trimethyl amine,and the like.

The amount of the used base is ordinarily 1 to 10 mole, and preferably 1to 3 mole with respect to 1 mole of the compound (XXII).

Examples of the used palladium catalyst include Pd(PPh₃)₄, Pd(OAc)₂,Pd₂(dba)₃, PdCl₂(PPh₃)₂, and the like.

The amount of the used palladium catalyst is ordinarily 0.01 to 0.5mole, and preferably 0.05 to 0.2 mole with respect to 1 mole of thecompound (XXII).

Examples of the used phosphine ligand include PPh₃, P(o-tol)₃,P(tert-Bu)₃, 2-[di(tert-butyl)phosphino]-1,1′-biphenyl,2-[di(tert-butyl)phosphino]-2′-dimethylamino-1,1′-biphenyl,2-[dicyclohexylphosphino]-1,1′-biphenyl,2-[dicyclohexylphosphino]-2′-dimethylamino-1,1′-biphenyl, and the like.

The reaction temperature is ordinarily 0° C. to 200° C., and preferably25° C. to 130° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asdimethylformamide, tetrahydrofuran, dimethoxyethane, 1,4-dioxane,acetonitrile, and toluene.

Scheme 28 below is a synthesis method of the compound represented byFormula (II-3) wherein X is a single bond and Y is —CF₂—(CH₂)_(p)—(herein p is any integer of 0 to 5) in the compound of Formula (II).

Scheme 28: Method of manufacturing compound of Formula (II-3) fromFormula (II-2)

The compound of Formula (II-3) [in the formula, R¹, W¹, W², W³, W⁴, andW⁵ are as described above, and p is any integer of 0 to 5, and PG² is aprotective group.] can be obtained by fluorination of the compoundrepresented by Formula (II-2) [in the formula, R¹, W¹, W², W³, W⁴, andW⁵ are as described above, and p is any integer of 0 to 5, and PG² is aprotective group.]. More specifically, the compound (II-3) can beobtained by reacting the compound (II-2) with a fluorinating agent suchas diethyl aminosulfur trifluoride (DAST).

In the reaction, ordinarily 1 to 10 mole, and preferably 1 to 3 mole ofthe fluorinating agent is used with respect to 1 mole of the compound(II-2).

Examples of the fluorinating agent include diethyl aminosulfurtrifluoride (DAST), bis(2-methoxyethyl)aminosulfur trifluoride,1,1,2,2-tetrafluoroethyl-N,N-dimethylamine, diethylaminodifluorosulfinium tetrafluoroborate, morpholinodifluorosulfiniumtetrafluoroborate, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride,and the like.

The reaction temperature is ordinarily 0° C. to 200° C., and preferably25° C. to 130° C.

The reaction solvent is not particularly limited as long as it has noadverse effect on the reaction, but is preferably a solvent such asdichloromethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,acetonitrile, and toluene.

Next, the URAT1 inhibitor, the blood uric acid level-reducing agent, andthe pharmaceutical composition for treating or preventing pathologicalconditions associated with the blood uric acid of the present inventionwill be described.

The “URAT1” used in this specification represents the uric acidtransporter 1 (Uric acid transporter 1).

The “inhibiting URAT1” used in this specification means inhibiting thefunction as the uric acid transporter of URAT1 to cause the activitythereof to disappear or to be reduced, and, for example, it meansspecifically inhibiting the function of URAT1 based on the conditions ofExample 187 described below.

The “URAT1 inhibitor” used in this specification means a drug thatcontains the compound of Formula (I) (containing the form of apharmaceutically acceptable salt or an ester of the compound), andinhibits the function as the uric acid transporter of URAT1 whereby tocause the activity thereof to disappear or to be reduced.

The “blood uric acid level-reducing agent” used in this specificationmeans a drug that contains the compound of Formula (I) (containing theform of a pharmaceutically acceptable salt or an ester of the compound),and inhibits URAT1, whereby to reduce the blood uric acid level.

The “reducing the blood uric acid level” used in this specificationmeans reducing the uric acid (containing urate) in the blood (containingthe serum or the plasma) by inhibiting the function of URAT1 as the uricacid transporter, preferably reducing high serum uric acid level, morepreferably reducing the serum uric acid level to less than 8 mg/dL(preferably less than 7 mg/dL, and further preferably less than 6 mg/dLas the serum uric acid level).

The “high blood uric acid level” used in this specification means thatthe serum uric acid level is 6 mg/dL or more, preferably 7 mg/dL ormore, and more preferably 8 mg/dL or more.

The “pharmaceutical composition for treating or preventing pathologicalconditions associated with the blood uric acid” used in thisspecification means a pharmaceutical composition that contains thecompound of Formula (I) (containing the form of a pharmaceuticallyacceptable salt or an ester of the compound), and inhibits URAT1,whereby to treat or prevent pathological conditions associated with theblood uric acid.

The “pathological conditions associated with the blood uric acid” usedin this specification refers to pathological conditions associated withthe above-mentioned “high blood uric acid level”, and examples thereofinclude hyperuricemia, gouty node, acute gout arthritis, chronic goutarthritis, gouty kidney, urolithiasis, a renal function disorder, acoronary artery disease, an ischemic heart disease, and the like.

Any one of the URAT1 inhibitor, the blood uric acid level-reducing agentand the pharmaceutical composition for treating or preventingpathological conditions associated with the blood uric acid can beprovided as a formulation.

The “formulation” encompasses oral formulations and parenteralformulations. The oral formulation is, for example, a tablet, a capsule,a powder, a granule, and the like, and the parenteral formulation is,for example, a sterilized liquid formulation such as a solution or asuspension, specifically, an injection, a drop, and the like, andpreferably, an intravenous injection or an intravenous infusion.

The “formulation” of the present invention may contain ordinarily, atherapeutically effective dose of the compound of the present inventionalong with a pharmaceutically acceptable carrier or diluent. Thisformulation technique is regarded as a technique of common knowledge toone of ordinarily skill in the art, and is well known. Preferably, theformulation may be performed for an oral formulation, an intravenousinfusion or an injection with a lot of methods well known to one ofordinarily skill in the art together with a pharmaceutically acceptablecarrier or diluent.

Examples of the “pharmaceutically acceptable carrier or diluent” includean excipient (for example, fat, beeswax, polyol of semi-solid andliquid, natural or hardened oil and the like); water (for example,distilled water, particularly, distilled water for injection, and thelike), physiological saline, alcohol (for example, ethanol), glycerol,polyol, an aqueous solution of glucose, mannitol, vegetable oil, and thelike; additives (for example, a filler, a disintegrant, a binder, alubricant, a wetting agent, a stabilizer, an emulsifier, a dispersingagent, a preservative, a sweetener, a colorant, a seasoning agent or anaromatic substance, a thickening agent, a diluent, a buffering agent, asolvent or a solubilizer, an agent for accomplishing the storage effect,a salt for changing the osmotic pressure, a coating agent, or ananti-oxidant) and the like.

The formulation of the present invention may select various forms.Examples thereof include oral formulations such as, for example, atablet, a capsule, a powder, a granule or a solution, sterilized-liquidparenteral formulations such as a solution or a suspension, asuppository, an ointment, and the like.

The formulation of the present invention may be a solid formulation, ora liquid formulation.

The solid formulation may be manufactured as it is as a form of atablet, a capsule, a granule or a powder, or may be manufactured using aproper carrier (additive). Examples of such a carrier (additive)include: saccharides such as lactose or glucose; starches of corn,wheat, rice, and the like; a fatty acid such as a stearic acid; aninorganic salt such as magnesium aluminometasilicate or phosphoricanhydride calcium; synthetic macromolecules such as apolyvinylpyrrolidone or a polyalkylene glycol; a fatty acid salt such ascalcium stearate or a magnesium stearate; alcohols such as a stearylalcohol or benzyl alcohol; synthetic cellulosic derivatives such asmethylcellulose, carboxymethyl cellulose, ethyl cellulose, orhydroxypropyl methylcellulose; and other additives for general use suchas gelatin, talc, vegetable oil, and gum arabic, and the like.

Such solid formulation such as a tablet, a capsule, a granule and apowder may generally contain, for example, 0.1 to 100% by mass,preferably 5 to 98% by mass of the compound represented by Formula (I)based on the total mass of the formulation as an active ingredient.

The liquid formulation is manufactured as a form such as a suspension, asyrup, an injection, and a drop (intravenous infusion solution) by usingproper additives that are ordinarily used in the liquid formulation suchas water, alcohols and a vegetable-derived oil such as soybean oil,peanut oil and sesame oil.

Particularly, examples of the proper solvent or diluent whenadministered in a form of parenteral intramuscular injection,intravenous injection or subcutaneous injection include, for example,distilled water for injection, an aqueous solution of lidocainehydrochloride (for intramuscular injection), physiological saline, anaqueous solution of glucose, ethanol, polyethylene glycol, propyleneglycol, a liquid for intravenous injection (for example, an aqueoussolution of citric acid, sodium citrate, and the like), an electrolyticsolution (for intravenous infusion and for intravenous injection) andthe like, and a mixed solution thereof.

These injections may be in a form that is dissolved at the time of useas a powder of the active ingredient as it is or a powder of the activeingredient added with a proper carrier (additive), in addition to a formin which the active ingredient is preliminarily dissolved. Theseinjection liquids may contain, for example, 0.1 to 10% by mass of theactive ingredient based on the total mass of the formulation.

In addition, a solution for oral administration such as a suspension anda syrup may contain, respectively, for example, 0.1 to 10% by mass ofthe active ingredient based on the total mass of the formulation.

The compound of the present invention, the URAT1 inhibitor, the blooduric acid level-reducing agent, and the pharmaceutical composition fortreating or preventing pathological conditions associated with uric acidof the present invention may be used in combination with anotherpharmaceutical composition or drug (hereinafter, also referred to as thecombination drug).

The “combination” means combination use of multiple drugs as an activeingredient. For example, examples of the “combination use” include useas a combination preparation, use as a kit, use in combination which ischaracterized by separate, respective administration through identicalor different administration route, and the like.

The administration time of the compound of the present invention, theURAT1 inhibitor, and the blood uric acid level-reducing agent and thepharmaceutical composition for treating or preventing pathologicalconditions associated with the blood uric acid of the present invention,and the combination drug is not limited, and they may be administeredsimultaneously, or may be administered at staggered time to anadministration subject. The dose of the combination drug may be inaccordance to a dose that is clinically used, and may be appropriatelyselected depending on a subject to be administered, the age and theweight of the subject to be administered, the symptom, theadministration time, the formulation, the administering method, thecombination and the like. The administration form of the combinationdrug is not limited, as long as the URAT1 inhibitor, the blood uric acidlevel-reducing agent or the pharmaceutical composition for treatment ofpathological conditions associated with the blood uric acid of thepresent invention is combined with a combination drug at the time of theadministration.

Examples of the combination drug include “an agent for treating and/orpreventing hyperuricemia”, “an agent for treating and/or preventing goutarthritis”, “an agent for treating and/or preventing gouty kidney”, “anagent for treating and/or preventing urolithiasis”, “an agent fortreating and/or preventing hypertension or hypertension complication”,“an agent for treating and/or preventing hyperlipidaemia orhyperlipidaemia complication”, “an agent for treating and/or preventingdiabetes or diabetic complication”, “an agent for treating and/orpreventing obesity or obesity complication”, “an agent for treatingand/or preventing a primary disease that causes secondaryhyperuricemia”, “an agent for treating and/or preventing renal failure,a cardiovascular disorder or a cerebrovascular disorder caused byhyperuricemia” and “a nucleic acid metabolism antagonist”. One to threeof these combination drugs may be used in combination with the URAT1inhibitor, the blood uric acid level-reducing agent and thepharmaceutical composition for treating or preventing pathologicalconditions associated with the blood uric acid of the present invention.

Examples of the “agent for treating and/or preventing hyperuricemia”include an agent for suppressing production of uric acid such as anxanthine oxidase inhibitor, an uric acid excretion facilitator and thelike. Specifically, the examples include allopurinol, probenecid,bucolome, febuxostat, FYX-051(4-(5-pyridin-4-yl-1H-[1,2,4]triazole-3-yl)pyridin-2-carbonitrile),benzbromarone, oxypurinol, and the like.

Examples of the “agent for treating and/or preventing gout arthritis”include non-steroidal anti-inflammatory agents such as indometacin,naproxen, fenbufen, pranoprofen, and oxaprozin; colchicine; anadrenocortical steroid, and the like.

Examples of the “agent for treating and/or preventing gouty kidney”include an agent for suppressing production of uric acid such as anxanthine oxidase inhibitor; an uric acid excretion facilitator; a citricacid formulation; an uric alkalifying agent such as sodium bicarbonate,and the like. Specifically, the examples include allopurinol,probenecid, bucolome, febuxostat, FYX-051(4-(5-pyridin-4-yl-1H-[1,2,4]triazole-3-yl)pyridin-2-carbonitrile),benzbromarone, oxypurinol, and the like.

Examples of the “agent for treating and/or preventing urolithiasis”include a citric acid formulation; an uric alkalifying agent such assodium bicarbonate, and the like.

Examples of the “agent for treating and/or preventing hypertension orhypertension complication” include a loop diuretic agent, an angiotensinconversion enzyme inhibitor, an angiotensin II receptor antagonist, a Caantagonist, a β blocker, a α, μ blocker, a α blocker, and the like. Morespecifically, for example, a furosemide sustained release drug,captopril, a captopril sustained release drug, enalapril maleate,alacepril, delapril hydrochloride, cilazapril, lisinopril, benazeprilhydrochloride, imidapril hydrochloride, temocapril hydrochloride,quinapril hydrochloride, trandolapril, perindopril erbumine, losartanpotassium, candesartan cilexetil, nicardipine hydrochloride, nicardipinehydrochloride sustained release drug, nilvadipine, nifedipine,nifedipine sustained release drug, benidipine hydrochloride, diltiazemhydrochloride, diltiazem hydrochloride sustained release drug,nisoldipine, nitrendipine, manidipine hydrochloride, barnidipinehydrochloride, efonidipine hydrochloride, amlodipine besylate,felodipine, cilnidipine, aranidipine, propranolol hydrochloride,propranolol hydrochloride sustained release drug, pindolol, a pindololsustained release drug, indenolol hydrochloride, carteololhydrochloride, a carteolol hydrochloride sustained release drug,bunitrolol hydrochloride, a bunitrolol hydrochloride sustained releasedrug, atenolol, acebutolol hydrochloride, metoprolol tartrate, ametoprolol tartrate sustained release drug, nipradilol, penbutololsulfate, tilisolol hydrochloride, carvedilol, bisoprolol fumarate,betaxolol hydrochloride, celiprolol hydrochloride, bopindolol malonate,bevantolol hydrochloride, labetalol hydrochloride, arotinololhydrochloride, amosulalol hydrochloride, prazosin hydrochloride,terazosin hydrochloride, doxazosin mesilate, bunazosin hydrochloride, abunazosin hydrochloride sustained release drug, urapidil, phentolaminemesilate, and the like are included.

Examples of the “agent for treating and/or preventing hyperlipidaemia orhyperlipidaemia complication” include a HMG-CoA reduction enzymeinhibitor, an anion exchange resin, probucol, a nicotinic acidformulation, a fibrate-based drug, an eicosapentaenoic acid formulation,and the like. More specifically, for example, lovastatin, simvastatin,pravastatin, fluvastatin, atorvastatin, cerivastatin, colestimide,cholestyramine, niceritrol, nicomol, fenofibrate, bezafibrate,clinofibrate, clofibrate, ethyl icosapentate, and the like are included.

Examples of the “agent for treating and/or preventing diabetes ordiabetic complication” include an insulin formulation, a sulfonyl ureaagent, an insulin secretion facilitator, a sulfone amide agent, abiguanide agent, an a glucosidase inhibitor, an insulinresistance-improving agent, a dipeptidyl peptidase IV inhibitor, anangiotensin conversion enzyme inhibitor, an aldose reduction enzymeinhibitor, an anti-arrhythmia agent, and the like. More specifically,for example, insulin, chlorpropamide, glibenclamide, glipizide,tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide,gliclazide, nateglinide, glybuzole, metformin hydrochloride, buforminhydrochloride, voglibose, acarbose, pioglitazone hydrochloride,sitagliptin phosphate, vildagliptin, allogliputin mexiletine benzoicacid, epalrestat, and the like are included.

Examples of the “agent for treating and/or preventing obesity or obesitycomplication” include mazindole, acarbose, voglibose, eparestat, and thelike.

Examples of the “agent for treating and/or preventing a primary diseasethat causes uric acid excretion reduction type secondary hyperuricemia”include, for example, an agent for treating or preventing a chronicrenal disease, polycystic kidney, toxemia of pregnancy, leadnephropathy, hyperlacticacidemia, Down's syndrome, sarcoidosis, Type Iglycogenosis (via hyperlacticacidemia), dehydration, and the like.

Examples of the “agent for treating and/or preventing renal failure, acardiovascular disorder or a cerebrovascular disorder caused byhyperuricemia” include a loop diuretic agent (for example, furosemide),a citric acid formulation, sodium bicarbonate, a cationic exchangeresin, aluminum hydroxide, alfacalcidol, a β-blocker (for example,propranolol hydrochloride), an angiotensin conversion enzyme inhibitor(for example, captopril), a cardiotonic agent (for example, digoxin), anagent for treating angina pectoris (for example, isosorbide nitrate), aCa antagonist (for example, diltiazem hydrochloride), an agent forsuppressing production of uric acid (for example, allopurinol), an aminoacid formulation, a hyperammonemia-improving agent, an agent fortreating arrhythmia (for example, mexiletine), an agent for treatinganemia (for example, mepitiostane, erythropoietin), and in addition, the“agent for treating and/or preventing hypertension or hypertensioncomplication”, the “agent for treating and/or preventing hyperlipidaemiaor hyperlipidaemia complication”, the “agent for treating and/orpreventing diabetes or diabetic complication”, the “agent for treatingand/or preventing obesity or obesity complication”, and the like.

Examples of the “nucleic acid metabolism antagonist” includeazathiopurine, mizoribine, mycophenolic acid, and the like.

In addition, any one of the compound of the present invention, the URAT1inhibitor, the blood uric acid level-reducing agent, and thepharmaceutical composition for treating or preventing pathologicalconditions associated with uric acid of the present invention, canreduce the blood uric acid level in combination use with a drug thatleads to increase of the blood uric acid level.

Examples of the “drug that leads to increase of the blood uric acidlevel” include a nucleic acid metabolism antagonist, a hypotensivediuretic agent (for example, furosemide and a thiazide-based diureticagent), an anti-tuberculosis agent (for example, pyrazinamide andethambutol), an anti-inflammatory analgesic agent (for example,salicylic acid), a hyperlipidaemia agent (for example, nicotinic acid),an agent for treating asthma (for example, theophylline), animmunosuppressive agent (for example, cyclosporine), an agent fortreating type C hepatitis (for example, ribavirin), ethanol, and thelike.

EXAMPLE

The present invention will be further specifically described withExamples below, but the present invention is not limited to theseExamples. For various reagents used in Examples, commercial productswere used unless stated otherwise. For the thin layer chromatography inExamples, Silica gel₆₀ F₂₅₄ manufactured by MERCK KGaA was used as theplate, and a UV detector was used as the detection method. For thesilica gel column chromatography, Biotage (registered trademark) SNAPCartridge KP-Sil silica gel prepacked column manufactured by Biotage, orChromatorex (registered trademark) Q-PACK COOH silica gel prepackedcolumn manufactured by FUJI SILYSIA CHEMICAL LTD. was used. For thereverse phase preparative liquid chromatography, CombiPrep Pro C18manufactured by YMC CO., LTD. was used as the column, and 0.1%trifluoroacetic acid in water and 0.1% trifluoroacetic acid inacetonitrile were used as the mobile phase.

For ¹H-NMR, AL400 (400 MHz) manufactured by JEOL Ltd. was used, and¹H-NMR was measured using tetramethyl silane as a standard substance.The mass spectrum was measured with electrospray ionization (ESI) usingACQUITY (registered trademark) SQD manufactured by WATERS. The microwavereaction was performed using Initiator (registered trademark)manufactured by Biotage.

The meanings of the symbols are as described below.

s: Singlet

d: Doublet

t: Triplet

q: Quartet

dd: Double Doublet

dt: Double Triplet

td: Triple Doublet

tt: Triple Triplet

ddd: Double Double Doublet

ddt: Double Double Triplet

dtd: Double Triple Doublet

tdd: Triple Double Doublet

tq: Triple Quartet

m: Multiplet

br: Broad

DMSO-d₆: Deuterated dimethyl sulfoxide

CDCl₃: Deuterated chloroform

CD₃OD: Deuterated methanol

tBu: tert-butyl group

Example 1 Synthesis of 1-benzyl-1H-indole-6-carboxylic acid [1](hereinafter referred to as “a compound [1]”)

(1) Synthesis of methyl 1-benzyl-1H-indole-6-carboxylate [1-1](hereinafter referred to as a compound [1-1])

To a solution of methyl indole-6-carboxylate (1.0 g) inN,N-dimethylformamide (10 mL), potassium carbonate (1.2 g) and benzylchloride (1.4 g) were added at room temperature, and then the reactionmixture was stirred at 60° C. for 3 hours. After cooling to roomtemperature, the reaction mixture was quenched with water, and themixture was extracted with chloroform. The obtained organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (681 mg)as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 8.09 (1H, s), 7.81 (1H, dd, J=8.3, 1.5 Hz),7.66 (1H, d, J=8.3 Hz), 7.33-7.25 (4H, m), 7.12-7.09 (2H, m), 6.59 (1H,dd, J=3.2, 0.7 Hz), 5.38 (2H, s), 3.91 (3H, s).

(2) Synthesis of 1-benzyl-1H-indole-6-carboxylic acid [1]

To a solution of the compound [1-1] obtained in the process (1) (681 mg)in ethanol (30 mL), an aqueous solution of 1 N-sodium hydroxide (10 mL)was added, and then the reaction mixture was stirred at 50° C. for 18hours. After cooling to room temperature, to the reaction mixture wasadded 1 N-hydrochloric acid for acidification, and extracted withchloroform. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (453 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.17 (1H, s), 7.87 (1H, dd, J=8.3, 1.5 Hz),7.69 (1H, d, J=8.5 Hz), 7.35-7.24 (3H, m), 7.26 (1H, d, J=0.5 Hz), 7.13(2H, d, J=7.1 Hz), 6.61 (1H, d, J=3.2 Hz), 5.41 (2H, s).

Example 2 Synthesis of 1-(2,6-dimethylbenzyl)-1H-indole-6-carboxylicacid [2] (hereinafter referred to as the compound [2])

(1) Synthesis of methyl 1-(2,6-dimethylbenzyl)-1H-indole-6-carboxylate[2-1] (hereinafter referred to as the compound [2-1])

The titled compound (7.4 g) as a white solid was prepared from methylindole-6-carboxylate (5.0 g) and 2,6-dimethylbenzyl chloride (5.3 g)according to the method of the process (1) of Example 1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.30 (1H, s), 7.84 (1H, dd, J=8.3, 1.5 Hz),7.65 (1H, d, J=8.3 Hz), 7.23 (1H, dd, J=8.4, 6.8 Hz), 7.14 (2H, d, J=7.6Hz), 6.74 (1H, d, J=3.2 Hz), 6.44 (1H, dd, J=3.2, 1.0 Hz), 5.32 (2H, s),3.98 (3H, s), 2.26 (6H, s).

(2) Synthesis of 1-(2,6-dimethylbenzyl)-1H-indole-6-carboxylic acid [2]

The titled compound (883 mg) as a white solid was prepared from thecompound [2-1] obtained in the process (1) (1.0 g) according to themethod of the process (2) of Example 1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.37 (1H, s), 7.91 (1H, dd, J=8.4, 1.3 Hz),7.68 (1H, d, J=8.3 Hz), 7.22 (1H, dd, J=8.4, 7.2 Hz), 7.14 (2H, d, J=7.6Hz), 6.78 (1H, d, J=3.2 Hz), 6.47 (1H, dd, J=3.0, 0.9 Hz), 5.34 (2H, s),2.27 (6H, s).

Example 3 Synthesis of 1-(2,4,6-trimethylbenzyl)-1H-indole-6-carboxylicacid [3] (hereinafter referred to as the compound [3])

The titled compound (790 mg) as a pale yellow solid was prepared frommethyl indole-6-carboxylate (1.0 g) and 2,4,6-trimethylbenzyl chloride(1.2 g) according to the method of Example 1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.38 (1H, s), 7.92 (1H, dd, J=8.4, 1.3 Hz),7.68 (1H, d, J=8.3 Hz), 6.96 (2H, s), 6.80 (1H, d, J=3.2 Hz), 6.46 (1H,dd, J=3.0, 0.6 Hz), 5.30 (2H, s), 2.33 (3H, s), 2.23 (6H, s).

Example 4 Synthesis of 2-(1-benzyl-1H-indole-6-yl)acetic acid [4](hereinafter referred to as a compound [4])

(1) Synthesis of methyl 1-tosyl-1H-indole-6-carboxylate [4-1](hereinafter referred to as a compound [4-1])

To a solution of methyl indole-6-carboxylate (2.1 g) of 2-pentanone (40mL), potassium carbonate (6.5 g) and 4-methylbenzenesulfonyl chloride(4.4 g) were added at room temperature, and then the reaction mixturewas stirred at 80° C. for 16 hours. After cooling to room temperature,the insoluble materials were filtered, and the filtrate was concentratedunder reduced pressure. To the obtained residue, a mixed solvent ofethyl acetate-hexane was added, and the obtained solid was filtered, andwashed with hexane to give the titled compound (3.6 g) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.69 (1H, s), 7.93 (1H, dd, J=8.2, 1.3 Hz),7.80 (2H, d, J=8.3 Hz), 7.71 (1H, d, J=3.7 Hz), 7.56 (1H, d, J=8.3 Hz),7.24 (2H, d, J=8.3 Hz), 6.69 (1H, d, J=3.4 Hz), 3.97 (3H, s), 2.35 (3H,s).

(2) Synthesis of (1-tosyl-1H-indole-6-yl)methanol [4-2] (hereinafterreferred to as a compound [4-2])

Lithium aluminum hydride (505 mg) was added to tetrahydrofuran (70 mL).To the suspension was dropped a solution of the compound [4-1] obtainedin the process (1) (3.5 g) in tetrahydrofuran (70 mL) at 0° C., and thenthe reaction mixture was stirred at 0° C. for 3 hours. To the reactionmixture was added sodium sulfate 10 hydrate, filtered through a pad ofcelite, and the filtrate was concentrated under reduced pressure to givethe titled compound (3.4 g) as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 7.99 (1H, s), 7.77 (2H, d, J=10.0 Hz), 7.57(1H, d, J=2.9 Hz), 7.51 (1H, d, J=8.1 Hz), 7.25-7.20 (3H, m), 6.64 (1H,d, J=3.4 Hz), 4.79 (2H, s), 2.34 (3H, s), 1.80-1.70 (1H, brs).

(3) Synthesis of 6-(chloromethyl)-1-tosyl-1H-indole [4-3] (hereinafterreferred to as a compound [4-3])

To a solution of the compound [4-2] obtained in the process (2) (3.3 g)in chloroform (40 mL) were added triethylamine (2.4 mL) andmethanesulfonyl chloride (1.1 mL) at 0° C., and then the reactionmixture was stirred at room temperature for 27 hours. To the reactionmixture was added a saturated aqueous solution of sodium hydrogencarbonate, and extracted with chloroform. The obtained organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure to give the titled compound (3.8 g)as a brown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.03 (1H, s), 7.77 (2H, d, J=8.5 Hz), 7.58(1H, d, J=3.7 Hz), 7.51 (1H, d, J=8.1 Hz), 7.26 (1H, dd, J=8.1, 1.5 Hz),7.23 (2H, d, J=8.8 Hz), 6.64 (1H, d, J=3.7 Hz), 4.73 (2H, s), 2.35 (3H,s).

(4) Synthesis of 2-(1-tosyl-1H-indole-6-yl)acetonitrile [4-4](hereinafter referred to as a compound [4-4])

To a solution of the compound [4-3] obtained in the process (3) (3.8 g)in dimethyl sulfoxide (40 mL) was added sodium cyanide (652 mg) at roomtemperature, and then the reaction mixture was stirred at roomtemperature for 48 hours. The reaction mixture was quenched with water,and extracted with ethyl acetate. The obtained organic layer was driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (2.4 g)as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 7.95 (1H, s), 7.77 (2H, d, J=8.3 Hz), 7.59(1H, d, J=3.7 Hz), 7.53 (1H, d, J=8.1 Hz), 7.25 (2H, d, J=7.8 Hz), 7.20(1H, dd, J=7.9, 1.8 Hz), 6.65 (1H, d, J=3.7 Hz), 3.87 (2H, s), 2.35 (3H,s).

(5) Synthesis of 2-(1H-indole-6-yl)acetic acid [4-5] (hereinafterreferred to as a compound [4-5])

To a solution of the compound [4-4] obtained in the process (4) (2.4 g)in ethanol (12 mL) was added an aqueous solution of 5 N-sodium hydroxide(12 mL) at room temperature, and then heated at reflux for 6 hours.After cooling to room temperature, the ethanol was concentrated underreduced pressure, and then the obtained aqueous phase was washed withdiethylether. Then, concentrated hydrochloric acid (5 mL) was dropped at0° C. for acidification, and the precipitate was filtered. The obtainedsolid was dissolved in a mixed solvent of chloroform-methanol, driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure to give the titled compound (980 mg)as a colorless oil.

¹H-NMR (400 MHz, CD₃OD) δ: 10.40 (1H, s), 7.47 (1H, d, J=7.3 Hz), 7.30(1H, s), 7.20-7.15 (1H, m), 6.93 (1H, dd, J=8.2, 2.1 Hz), 6.39 (1H, s),3.65 (2H, s).

(6) Synthesis of methyl 2-(1H-indole-6-yl)acetate [4-6] (hereinafterreferred to as a compound [4-6])

To a solution of the compound [4-5] obtained in the process (5) (497 mg)in N,N-dimethylformamide (10 mL) were added potassium carbonate (511 mg)and methyl iodide (0.12 mL) at 0° C., and then the reaction mixture wasstirred at room temperature for 13 hours. The reaction mixture wasquenched with water, and extracted with ethyl acetate. The obtainedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titledcompound (512 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 8.25-8.00 (1H, br), 7.59 (1H, d, J=8.1 Hz),7.33 (1H, d, J=0.7 Hz), 7.19 (1H, t, J=2.8 Hz), 7.04 (1H, dd, J=8.1, 1.2Hz), 6.53 (1H, s), 3.73 (2H, s), 3.69 (3H, s).

(7) Synthesis of 2-(1-benzyl-1H-indole-6-yl)acetic acid [4]

To a solution of the compound [4-6] obtained in the process (6) (49 mg)in acetonitrile (2 mL) were added powdered potassium hydroxide (19 mg)and benzyl chloride (0.033 mL) at room temperature, and then thereaction mixture was subjected to microwave irradiation at 140° C. for20 minutes. To this reaction mixture were added methanol (1 mL) and anaqueous solution of 1 N-sodium hydroxide (1 mL), and the reactionmixture was subjected to microwave irradiation at 140° C. for 10minutes. To the reaction mixture was added 4 N-hydrochloric acid foracidification, and then the reaction mixture was extracted with ethylacetate. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (42 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.44 (1H, d, J=8.3 Hz), 7.31 (1H, s),7.28-7.10 (6H, m), 7.03 (1H, dd, J=8.3, 1.5 Hz), 6.41 (1H, dd, J=3.2,1.0 Hz), 5.36 (2H, s), 3.53 (2H, s).

ESI-MS found: 266 [M+H]⁺

Example 5 Synthesis of 2-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]aceticacid [5] (hereinafter referred to as a compound [5])

The titled compound (81 mg) was prepared from the compound [4-6]obtained in the process (6) of Example 4 (97 mg) and 2,6-dimethylbenzylchloride (79 mg) according to the method of the process (7) of Example4.

¹H-NMR (400 MHz, CD₃OD) δ: 7.52-7.44 (2H, m), 7.21-7.14 (1H, m), 7.10(2H, d, J=7.6 Hz), 7.00 (1H, dd, J=8.2, 1.1 Hz), 6.56 (1H, d, J=3.2 Hz),6.32 (1H, d, J=3.2 Hz), 5.29 (2H, s), 3.72 (2H, s), 2.24 (6H, s).

ESI-MS found: 293[M+H]⁺

Example 6 Synthesis of 2-[1-(2-methylbenzyl)-1H-indole-6-yl]acetic acid[6] (hereinafter referred to as a compound [6])

The titled compound (39 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (50 mg) and2-methylbenzyl chloride (44 μL) according to the method of the process(7) of Example 4.

¹H-NMR (400 MHz, CD₃OD) δ: 7.51 (1H, d, J=8.1 Hz), 7.23 (1H, s),7.21-7.12 (2H, m), 7.08-7.02 (2H, m), 6.98 (1H, dd, J=8.3, 1.7 Hz), 6.68(1H, d, J=7.8 Hz), 6.45 (1H, dd, J=3.2, 0.7 Hz), 5.34 (2H, s), 3.64 (2H,s), 2.29 (3H, s).

ESI-MS found: 280 [M+H]⁺

Example 7 Synthesis of 2-[1-(2-chlorobenzyl)-1H-indole-6-yl]acetic acid[7] (hereinafter referred to as a compound [7])

The titled compound (39 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (49 mg) and2-chlorobenzyl chloride (42 μL) according to the method of the process(7) of Example 4.

¹H-NMR (400 MHz, CD₃OD) δ: 7.53 (1H, d, J=8.1 Hz), 7.43 (1H, dd, J=8.1,1.2 Hz), 7.26-7.20 (3H, m), 7.12 (1H, td, J=7.5, 1.1 Hz), 7.00 (1H, dd,J=8.2, 1.3 Hz), 6.62 (1H, dd, J=7.7, 1.1 Hz), 6.50 (1H, dd, J=3.2, 0.7Hz), 5.47 (2H, s), 3.63 (2H, s).

ESI-MS found: 300[M+H]⁺

Example 8 Synthesis of2-{1-[2-(trifluoromethyl)benzyl]-1H-indole-6-yl}acetic acid [8](hereinafter referred to as a compound [8])

The titled compound (50 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (50 mg) and2-(trifluoromethyl)benzyl bromide (53 mg) according to the method of theprocess (7) of Example 4.

¹H-NMR (400 MHz, CD₃OD) δ: 7.73 (1H, d, J=6.1 Hz), 7.50 (1H, d, J=7.8Hz), 7.42-7.30 (2H, m), 7.20-7.10 (2H, m), 7.08 (1H, d, J=7.6 Hz),6.60-6.48 (2H, m), 5.59 (2H, s), 3.50 (2H, s).

ESI-MS found: 334 [M+H]⁺

Example 9 Synthesis of 2-[1-(2-fluorobenzyl)-1H-indole-6-yl]acetic acid[9] (hereinafter referred to as a compound [9])

The titled compound (22 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2-fluorobenzyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 284[M+H]⁺

Example 10 Synthesis of 2-[1-(3-fluorobenzyl)-1H-indole-6-yl]acetic acid[10] (hereinafter referred to as a compound [10])

The titled compound (47 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and3-fluorobenzyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 284[M+H]⁺

Example 11 Synthesis of 2-[1-(4-fluorobenzyl)-1H-indole-6-yl]acetic acid[11] (hereinafter referred to as a compound [11])

The titled compound (36 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and4-fluorobenzyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 284[M+H]⁺

Example 12 Synthesis of2-[1-(2-chloro-6-fluorobenzyl)-1H-indole-6-yl]acetic acid [12](hereinafter referred to as a compound [12])

The titled compound (40 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2-chloro-6-fluorobenzyl chloride according to the method of the process(7) of Example 4.

ESI-MS found: 318[M+H]⁺[M+H]⁺

Example 13 Synthesis of2-[1-(2-chloro-4-fluorobenzyl)-1H-indole-6-yl]acetic acid [13](hereinafter referred to as a compound [13])

The titled compound (38 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2-chloro-4-fluorobenzyl chloride according to the method of the process(7) of Example 4.

ESI-MS found: 318[M+H]⁺

Example 14 Synthesis of2-[1-(2-chloro-5-fluorobenzyl)-1H-indole-6-yl]acetic acid [14](hereinafter referred to as a compound [14])

The titled compound (24 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2-chloro-5-fluorobenzyl bromide according to the method of the process(7) of Example 4.

ESI-MS found: 318[M+H]⁺

Example 15 Synthesis of 2-[1-(3-chlorobenzyl)-1H-indole-6-yl]acetic acid[15] (hereinafter referred to as a compound [15])

The titled compound (20 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and3-chlorobenzyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 300[M+H]⁺

Example 16 Synthesis of 2-[1-(4-chlorobenzyl)-1H-indole-6-yl]acetic acid[16] (hereinafter referred to as a compound [16])

The titled compound (17 mg) as a light brown solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and4-chlorobenzyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 300[M+H]⁺

Example 17 Synthesis of 2-[1-(2,6-dichlorobenzyl)-1H-indole-6-yl]aceticacid [17] (hereinafter referred to as a compound [17])

The titled compound (65 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2,6-dichlorobenzyl chloride according to the method of the process (7)of Example 4.

ESI-MS found: 334[M+H]⁺

Example 18 Synthesis of 2-[1-(2,3-dichlorobenzyl)-1H-indole-6-yl]aceticacid [18] (hereinafter referred to as a compound [18])

The titled compound (13 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2,3-dichlorobenzyl chloride according to the method of the process (7)of Example 4.

ESI-MS found: 334[M+H]⁺

Example 19 Synthesis of2-{1-[(6-chlorobenzo[d][1,3]dioxol-5-yl)methyl]-1H-indole-6-yl}aceticacid [19] (hereinafter referred to as a compound [19])

The titled compound (46 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and6-chloropiperonyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 344[M+H]⁺

Example 20 Synthesis of 2-[1-(2,4-dichlorobenzyl)-1H-indole-6-yl]aceticacid [20] (hereinafter referred to as a compound [20])

The titled compound (29 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2,4-dichlorobenzyl chloride according to the method of the process (7)of Example 4.

ESI-MS found: 334[M+H]⁺

Example 21 Synthesis of 2-[1-(2,5-dichlorobenzyl)-1H-indole-6-yl]aceticacid [21] (hereinafter referred to as a compound [21])

The titled compound (17 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2,5-dichlorobenzyl bromide according to the method of the process (7) ofExample 4.

ESI-MS found: 334[M+H]⁺

Example 22 Synthesis of2-{1-[2-fluoro-6-(trifluoromethyl)benzyl]-1H-indole-6-yl}acetic acid[22] (hereinafter referred to as a compound [22])

The titled compound (16 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2-fluoro-6-(trifluoromethyl)benzyl bromide according to the method ofthe process (7) of Example 4.

ESI-MS found: 352[M+H]⁺

Example 23 Synthesis of2-{1-[4-fluoro-2-(trifluoromethyl)benzyl]-1H-indole-6-yl}acetic acid[23] (hereinafter referred to as a compound [23])

The titled compound (36 mg) as a reddish brown solid was prepared fromthe compound [4-6] obtained in the process (6) of Example 4 (100 mg) and4-fluoro-2-(trifluoromethyl)benzyl bromide according to the method ofthe process (7) of Example 4.

ESI-MS found: 352[M+H]⁺

Example 24 Synthesis of 2-[1-(4-ethylbenzyl)-1H-indole-6-yl]acetic acid[24] (hereinafter referred to as a compound [24])

The titled compound (24 mg) as a reddish brown solid was prepared fromthe compound [4-6] obtained in the process (6) of Example 4 (100 mg) and4-ethylbenzyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 294[M+H]⁺

Example 25 Synthesis of 2-[1-(2,4-difluorobenzyl)-1H-indole-6-yl]aceticacid [25] (hereinafter referred to as a compound [25])

The titled compound (35 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2,4-difluorobenzyl chloride according to the method of the process (7)of Example 4.

ESI-MS found: 302[M+H]⁺

Example 26 Synthesis of 2-[1-(2,6-difluorobenzyl)-1H-indole-6-yl]aceticacid [26] (hereinafter referred to as a compound [26])

The titled compound (20 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2,6-difluorobenzyl chloride according to the method of the process (7)of Example 4.

ESI-MS found: 302[M+H]⁺

Example 27 Synthesis of 2-[1-(2,5-difluorobenzyl)-1H-indole-6-yl]aceticacid [27] (hereinafter referred to as a compound [27])

The titled compound (18 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2,5-difluorobenzyl bromide according to the method of the process (7) ofExample 4.

ESI-MS found: 302[M+H]⁺

Example 28 Synthesis of 2-[1-(2,3-difluorobenzyl)-1H-indole-6-yl]aceticacid [28] (hereinafter referred to as a compound [28])

The titled compound (14 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2,3-difluorobenzyl bromide according to the method of the process (7) ofExample 4.

ESI-MS found: 302[M+H]⁺

Example 29 Synthesis of2-{1-[3-(trifluoromethyl)benzyl]-1H-indole-6-yl}acetic acid [29](hereinafter referred to as a compound [29])

The titled compound (38 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and3-(trifluoromethyl)benzyl chloride according to the method of theprocess (7) of Example 4.

ESI-MS found: 334[M+H]⁺

Example 30 Synthesis of2-{1-[4-(trifluoromethyl)benzyl]-1H-indole-6-yl}acetic acid [30](hereinafter referred to as a compound [30])

The titled compound (33 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and4-(trifluoromethyl)benzyl chloride according to the method of theprocess (7) of Example 4.

ESI-MS found: 334[M+H]⁺

Example 31 Synthesis of 2-[1-(2,4-dimethylbenzyl)-1H-indole-6-yl]aceticacid [31] (hereinafter referred to as a compound [31])

The titled compound (22 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2,4-dimethylbenzyl chloride according to the method of the process (7)of Example 4.

ESI-MS found: 294[M+H]⁺

Example 32 Synthesis of 2-[1-(2,5-dimethylbenzyl)-1H-indole-6-yl]aceticacid [32] (hereinafter referred to as a compound [32])

The titled compound (26 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2,5-dimethylbenzyl chloride according to the method of the process (7)of Example 4.

ESI-MS found: 294[M+H]⁺

Example 33 Synthesis of 2-[1-(3-methylbenzyl)-1H-indole-6-yl]acetic acid[33] (hereinafter referred to as a compound [33])

The titled compound (43 mg) as a reddish brown solid was prepared fromthe compound [4-6] obtained in the process (6) of Example 4 (100 mg) and3-methylbenzyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 280[M+H]⁺

Example 34 Synthesis of 2-[1-(4-methylbenzyl)-1H-indole-6-yl]acetic acid[34] (hereinafter referred to as a compound [34])

The titled compound (21 mg) as a reddish brown solid was prepared fromthe compound [4-6] obtained in the process (6) of Example 4 (100 mg) and4-methylbenzyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 280[M+H]⁺

Example 35 Synthesis of 2-[1-(pyridine-4-ylmethyl)-1H-indole-6-yl]aceticacid [35] (hereinafter referred to as a compound [35])

The titled compound (12 mg) as a yellow solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and4-(chloromethyl)pyridine according to the method of the process (7) ofExample 4.

ESI-MS found: 267[M+H]⁺

Example 36 Synthesis of 2-[1-(2-methoxybenzyl)-1H-indole-6-yl]aceticacid [36] (hereinafter referred to as a compound [36])

The titled compound (29 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2-methoxybenzyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 296[M+H]⁺

Example 37 Synthesis of 2-[1-(3-methoxybenzyl)-1H-indole-6-yl]aceticacid [37] (hereinafter referred to as a compound [37])

The titled compound (55 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and3-methoxybenzyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 296[M+H]⁺

Example 38 Synthesis of 2-[1-(4-methoxybenzyl)-1H-indole-6-yl]aceticacid [38] (hereinafter referred to as a compound [38])

The titled compound (44 mg) as a light brown solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and4-methoxybenzyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 296[M+H]⁺

Example 39 Synthesis of2-[1-(Naphthalene-1-ylmethyl)-1H-indole-6-yl]acetic acid [39](hereinafter referred to as a compound [39])

The titled compound (30 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and1-(chloromethyl)naphthalene according to the method of the process (7)of Example 4.

ESI-MS found: 316[M+H]⁺

Example 40 Synthesis of2-[1-(Naphthalene-2-ylmethyl)-1H-indole-6-yl]acetic acid [40](hereinafter referred to as a compound [40])

The titled compound (31 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2-(chloromethyl)naphthalene according to the method of the process (7)of Example 4.

ESI-MS found: 316[M+H]⁺

Example 41 Synthesis of2-{1-[(6-chloropyridine-3-yl)methyl]-1H-indole-6-yl}acetic acid [41](hereinafter referred to as a compound [41])

The titled compound (26 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2-chloro-5-(chloromethyl)pyridine according to the method of the process(7) of Example 4.

ESI-MS found: 301[M+H]⁺

Example 42 Synthesis of2-{1-[(6-methylpyridine-2-yl)methyl]-1H-indole-6-yl}acetic acid [42](hereinafter referred to as a compound [42])

The titled compound (26 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2-(bromomethyl)-6-methylpyridine according to the method of the process(7) of Example 4.

ESI-MS found: 281[M+H]⁺

Example 43 Synthesis of 2-[1-(biphenyl-2-ylmethyl)-1H-indole-6-yl]aceticacid [43] (hereinafter referred to as a compound [43])

The titled compound (41 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and2-phenylbenzyl bromide according to the method of the process (7) ofExample 4.

ESI-MS found: 342[M+H]⁺

Example 44 Synthesis of 2-[1-(biphenyl-3-ylmethyl)-1H-indole-6-yl]aceticacid [44] (hereinafter referred to as a compound [44])

The titled compound (46 mg) as an amorphous was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and3-phenylbenzyl bromide according to the method of the process (7) ofExample 4.

ESI-MS found: 342[M+H]⁺

Example 45 Synthesis of 2-[1-(biphenyl-4-ylmethyl)-1H-indole-6-yl]aceticacid [45] (hereinafter referred to as a compound [45])

The titled compound (22 mg) as a light brown solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and4-phenylbenzyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 342[M+H]⁺

Example 46 Synthesis of 2-[1-(3-phenoxybenzyl)-1H-indole-6-yl]aceticacid [46] (hereinafter referred to as a compound [46])

The titled compound (44 mg) as an amorphous substance was prepared fromthe compound [4-6] obtained in the process (6) of Example 4 (100 mg) and3-phenoxybenzyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 358[M+H]⁺

Example 47 Synthesis of 2-[1-(3-phenylpropyl)-1H-indole-6-yl]acetic acid[47] (hereinafter referred to as a compound [47])

The titled compound (44 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) and3-phenylpropyl chloride according to the method of the process (7) ofExample 4.

ESI-MS found: 294[M+H]⁺

Example 48 Synthesis of 2-(1-isopropyl-1H-indole-6-yl)acetic acid [48](hereinafter referred to as a compound [48])

The titled compound (12 mg) as an amorphous was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) andisopropyl chloride according to the method of the process (7) of Example4.

ESI-MS found: 218[M+H]⁺

Example 49 Synthesis of 2-(1-isobutyl-1H-indole-6-yl)acetic acid [49](hereinafter referred to as a compound [49])

The titled compound (10 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) andisobutyl chloride according to the method of the process (7) of Example4.

ESI-MS found: 232 [M+H]⁺

Example 50 Synthesis of 2-[1-(cyclohexylmethyl)-1H-indole-6-yl]aceticacid [50] (hereinafter referred to as a compound [50])

The titled compound (69 mg) as a white solid was prepared from thecompound [4-6] obtained in the process (6) of Example 4 (100 mg) andcyclohexylmethyl bromide according to the method of the process (7) ofExample 4.

ESI-MS found: 272 [M+H]⁺

Example 51 Synthesis of1-(2,6-dimethylbenzyl)-1H-benzimidazole-6-carboxylic acid [51](hereinafter referred to as a compound [51])

(1) Synthesis of 2,6-dimethylbenzyl1-(2,6-dimethylbenzyl)-1H-benzimidazole-6-carboxylate [51-1](hereinafter referred to as a compound [51-1])

To a solution of 5-benzoimidazole carboxylic acid (1.1 g) inN,N-dimethylformamide (15 mL) were added potassium carbonate (2.7 g) and2,6-dimethylbenzyl chloride (2.3 g) at room temperature, and then thereaction mixture was stirred at room temperature for 2 days. Thereaction mixture was quenched with water, and extracted with chloroform.The obtained organic layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive the titled compound (1.1 g) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.19 (1H, d, J=2.2 Hz), 8.01 (1H, dd, J=8.5,1.7 Hz), 7.80 (1H, d, J=8.5 Hz), 7.52 (1H, s), 7.24-7.22 (2H, m),7.13-7.11 (4H, m), 5.49 (2H, s), 5.31 (2H, s), 2.48 (6H, s), 2.26 (6H,s).

(2) Synthesis of 1-(2,6-dimethylbenzyl)-1H-benzimidazole-6-carboxylicacid [51]

To a solution of the compound [51-1] obtained in the process (1) (49 mg)in methanol (3 mL) was added an aqueous solution of 1 N-sodium hydroxide(3 mL) at room temperature, and then the reaction mixture was stirred at60° C. for 18 hours. After cooling to room temperature, to the reactionmixture was added 1N-hydrochloric acid for acidification, and theprecipitated solid was filtered to give the titled compound (30 mg) as awhite solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.16 (1H, d, J=1.2 Hz), 7.92 (1H, s), 7.83(1H, dd, J=8.5, 1.5 Hz), 7.71 (1H, d, J=8.5 Hz), 7.22 (1H, dd, J=8.3,6.8 Hz), 7.14 (2H, d, J=7.6 Hz), 5.52 (2H, s), 2.26 (6H, s).

Example 52 Synthesis of2-[1-(2,6-dimethylbenzyl)-1H-benzimidazole-6-yl]acetic acid [52](hereinafter referred to as a compound [52])

(1) Synthesis of [1-(2,6-dimethylbenzyl)-1H-benzimidazole-6-yl]methanol[52-1] (hereinafter referred to as a compound [52-1])

The titled compound (456 mg) as a white solid was prepared from thecompound [51-1] obtained in the process (1) of Example 51 (1.1 g) andlithium aluminum hydride (197 mg) according to the method of the process(2) of Example 4.

¹H-NMR (400 MHz, CDCl₃) δ: 7.78 (1H, d, J=8.3 Hz), 7.55 (1H, s), 7.38(1H, s), 7.29-7.26 (2H, m), 7.15 (2H, d, J=7.3 Hz), 5.28 (2H, s), 4.88(2H, d, J=4.9 Hz), 2.29 (6H, s), 1.95 (1H, s).

(2) Synthesis of2-[1-(2,6-dimethylbenzyl)-1H-benzimidazole-6-yl]acetonitrile [52-2](hereinafter referred to as a compound [52-2])

To a solution of the compound [52-1] obtained in the process (1) (408mg) in dichloromethane (10 mL) were added carbon tetrabromide (669 mg)and triphenylphosphine (525 mg) at room temperature, and then thereaction mixture was stirred at room temperature for 5 minutes. Then, tothe reaction mixture were added dimethyl sulfoxide (5 mL) and sodiumcyanide (109 mg), and the reaction mixture was stirred at 60° C. for 30minutes. The reaction mixture was quenched with water, and extractedwith chloroform. The organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (110 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.79 (1H, d, J=7.6 Hz), 7.49 (1H, s), 7.43(1H, s), 7.27 (1H, t, J=7.1 Hz), 7.21-7.15 (3H, m), 5.29 (2H, s), 3.93(2H, s), 2.29 (6H, s).

(3) Synthesis of 2-[1-(2,6-dimethylbenzyl)-1H-benzimidazole-6-yl]aceticacid [52]

To a solution of the compound [52-2] obtained in the process (2) (110mg) in ethanol (3 mL) was added an aqueous solution of 3N-sodiumhydroxide (3 mL) at room temperature, and then the reaction mixture washeated at reflux for 15 hours. To the reaction mixture was added1N-hydrochloric acid for acidification, and the precipitated solid wasfiltered to give the titled compound (81 mg) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 7.63 (1H, s), 7.57 (1H, d, J=8.3 Hz), 7.43(1H, s), 7.21 (1H, dd, J=8.2, 6.7 Hz), 7.13-7.09 (3H, m), 5.38 (2H, s),3.64 (2H, s), 2.24 (6H, s).

Example 53 Synthesis of 1-(2,6-dimethylbenzyl)-1H-indazole-6-carboxylicacid [53] (hereinafter referred to as a compound [53])

(1) Synthesis of 2,6-dimethylbenzyl1-(2,6-dimethylbenzyl)-1H-indazole-6-carboxylate [53-1] (hereinafterreferred to as a compound [53-1])

The titled compound (575 mg) as a yellow solid was prepared from1H-indazole-6-carboxylic acid (498 mg) and 2,6-dimethylbenzyl chloride(1.10 g) according to the method of the process (1) of Example 51.

¹H-NMR (400 MHz, CDCl₃) δ: 8.02 (1H, d, J=1.0 Hz), 7.87-7.86 (1H, m),7.77 (1H, dd, J=8.4, 1.3 Hz), 7.71 (1H, dd, J=8.5, 0.7 Hz), 7.24 (1H,dd, J=8.2, 6.7 Hz), 7.14 (2H, d, J=7.6 Hz), 7.08 (1H, dd, J=8.1, 7.1Hz), 6.96 (2H, d, J=7.6 Hz), 5.59 (2H, s), 5.42 (2H, s), 2.44 (6H, s),2.25 (6H, s).

(2) Synthesis of 1-(2,6-dimethylbenzyl)-1H-indazole-6-carboxylic acid[53]

The titled compound (51 mg) as a white solid was prepared from thecompound [53-1] obtained in the process (1) (110 mg) according to themethod of the process (2) of Example 51.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.33 (1H, d, J=1.2 Hz), 8.06 (1H, d, J=1.0Hz), 7.77 (1H, dd, J=8.4, 0.6 Hz), 7.70 (1H, dd, J=8.3, 1.2 Hz),7.14-7.12 (1H, m), 7.04 (2H, d, J=7.6 Hz), 5.62 (2H, s), 2.28 (6H, s).

Example 54 Synthesis of2-[1-(2,6-dimethylbenzyl)-1H-indazole-6-yl]acetic acid [54] (hereinafterreferred to as a compound [54])

(1) Synthesis of [1-(2,6-dimethylbenzyl)-1H-indazole-6-yl]methanol[54-1] (hereinafter referred to as a compound [54-1])

The titled compound (279 mg) as a white solid was prepared from thecompound [53-1] obtained in the process (1) of Example 53 (465 mg) andlithium aluminum hydride according to the method of the process (2) ofExample 4.

¹H-NMR (400 MHz, CDCl₃) δ: 7.96 (1H, s), 7.69 (1H, d, J=8.1 Hz),7.27-7.26 (1H, m), 7.19-7.17 (1H, m), 7.11-7.09 (3H, m), 5.54 (2H, s),4.79 (2H, d, J=5.9 Hz), 2.32 (6H, s), 1.82 (1H, t, J=5.6 Hz).

(2) Synthesis of 6-(bromomethyl)-1-(2,6-dimethylbenzyl)-1H-indazole[54-2] (hereinafter referred to as a compound [54-2])

To a solution of the compound [54-1] obtained in the process (1) (63 mg)in methylene chloride (3 mL) were added carbon tetrabromide (112 mg) andtriphenylphosphine (97 mg) at room temperature, and then the reactionmixture was stirred at room temperature for 10 minutes. The reactionmixture was concentrated under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography to give thetitled compound (72 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.97 (1H, d, J=1.0 Hz), 7.69 (1H, d, J=8.3Hz), 7.26-7.25 (1H, m), 7.22-7.16 (2H, m), 7.11 (2H, d, J=7.3 Hz), 5.54(2H, s), 4.60 (2H, s), 2.33 (6H, s).

(3) Synthesis of 2-[1-(2,6-dimethylbenzyl)-1H-indazole-6-yl]acetonitrile[54-3] (hereinafter referred to as a compound [54-3])

To a solution of the compound [54-2] obtained in the process (2) (250mg) in dimethyl sulfoxide (5 mL) was added sodium cyanide (62 mg) atroom temperature, and then the reaction mixture was stirred at 60° C.for 1 hour. The reaction mixture was quenched with water, and extractedwith ethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (152 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.98 (1H, d, J=1.0 Hz), 7.71 (1H, dd, J=8.3,0.7 Hz), 7.22-7.18 (2H, m), 7.11 (2H, d, J=7.6 Hz), 7.02 (1H, dd, J=8.5,1.7 Hz), 5.57 (2H, s), 3.84 (2H, s), 2.32 (6H, s).

(4) Synthesis of 2-[1-(2,6-dimethylbenzyl)-1H-indazole-6-yl]acetic acid[54]

The titled compound (154 mg) as a white solid was prepared from thecompound [54-3] obtained in the process (3) (148 mg) according to themethod of the process (3) of Example 52.

¹H-NMR (400 MHz, DMSO-d₆) δ: 7.94 (1H, s), 7.65 (1H, d, J=8.3 Hz), 7.60(1H, s), 7.11 (1H, dd, J=8.3, 6.6 Hz), 7.04-7.03 (3H, m), 5.49 (2H, s),3.65 (2H, s), 2.27 (6H, s).

Example 55 Synthesis of(E)-3-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]acrylic acid [55](hereinafter referred to as a compound [55])

(1) Synthesis of methyl(E)-3-(1H-indole-6-yl)acrylate [55-1](hereinafter referred to as a compound [55-1])

To a solution of indole-6-carboxaldehyde (499 mg) in tetrahydrofuran (20mL), methyl(triphenylphosphoranylidene)acetate (2.5 g) was added at roomtemperature, and then the reaction mixture was subjected to microwaveirradiation at 200° C. for 20 minutes. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography to give the titled compound(501 mg) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.33 (1H, s), 7.83 (1H, d, J=15.6 Hz), 7.64(1H, d, J=6.3 Hz), 7.55 (1H, s), 7.36 (1H, d, J=8.3 Hz), 7.31-7.29 (1H,m), 6.58 (1H, t, J=3.9 Hz), 6.46 (1H, dd, J=15.9, 1.5 Hz), 3.82 (3H, s).

(2) Synthesis ofmethyl(E)-3-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]acrylate [55-2](hereinafter referred to as a compound [55-2])

To a solution of the compound [55-1] obtained in the process (1) (61 mg)in N,N-dimethylformamide (2 mL), potassium carbonate (89 mg) and2,6-dimethylbenzyl chloride (81 mg) were added at room temperature, andthen the reaction mixture was subjected to microwave irradiation at 160°C. for 30 minutes. The reaction mixture was added with water, andextracted with ethyl acetate. The obtained organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography to give the titled compound (96 mg) as a yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.88 (1H, d, J=15.9 Hz), 7.61-7.59 (2H, m),7.36 (1H, dd, J=8.7, 1.3 Hz), 7.21 (1H, dd, J=8.7, 6.2 Hz) 7.12-7.09(2H, m), 6.68 (1H, d, J=3.4 Hz), 6.49 (1H, d, J=15.9 Hz), 6.40 (1H, d,J=3.2 Hz), 5.23 (2H, s), 3.81 (3H, s), 2.24 (6H, s).

(3) Synthesis of (E)-3-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]acrylicacid [55]

To a solution of the compound [55-2] obtained in the process (2) (96 mg)in methanol (3 mL), an aqueous solution of 1 N-sodium hydroxide (3 mL)was added at room temperature, and then the reaction mixture was stirredat 60° C. for 18 hours. After cooling to room temperature, and addedwith 1 N-hydrochloric acid for acidification, and the precipitated solidwas taken by filtration, whereby to give the titled compound (81 mg) asa yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.99 (1H, d, J=15.4 Hz), 7.65-7.64 (2H, m),7.41 (1H, dd, J=8.3, 1.7 Hz), 7.26-7.22 (1H, m), 7.14 (2H, d, J=7.8 Hz),6.71 (1H, d, J=3.2 Hz), 6.52 (1H, d, J=15.6 Hz), 6.43 (1H, d, J=3.2 Hz),5.28 (2H, s), 2.27 (6H, s).

Example 56 Synthesis of3-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]propionic acid [56](hereinafter referred to as a compound [56])

(1) Synthesis of methyl 3-(1H-indole-6-yl)propionate [56-1] (hereinafterreferred to as a compound [56-1])

To a solution of the compound [55-1] obtained in the process (1) ofExample 55 (98 mg) in methanol (3 mL), 5% palladium on carbon (103 mg)was added, and then the reaction mixture was stirred at room temperaturefor 4 hours under hydrogen atmosphere. The palladium on carbon wasseparated by filtration, and then the filtrate was concentrated underreduced pressure, whereby to give the titled compound (89 mg) as acolorless liquid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.14 (1H, s), 7.57 (1H, d, J=8.3 Hz), 7.23(1H, s), 7.17-7.16 (1H, m), 6.98 (1H, dd, J=8.1, 1.5 Hz), 6.53-6.51 (1H,m), 3.68 (3H, s), 3.07 (2H, t, J=7.8 Hz), 2.70 (2H, t, J=7.8 Hz).

(2) Synthesis of methyl3-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]propionate [56-2] (hereinafterreferred to as a compound [56-2])

To a solution of the compound [56-1] obtained in the process (1) (89 mg)in N,N-dimethylformamide (2 mL), potassium carbonate (116 mg) and2,6-dimethylbenzyl chloride (93 mg) were added at room temperature, andthen the reaction mixture was subjected to microwave irradiation at 160°C. for 30 minutes. The reaction mixture was quenched with water, andextracted with ethyl acetate. The obtained organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography to give the titled compound (75 mg) as a yellowliquid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.57 (1H, d, J=8.1 Hz), 7.34 (1H, s), 7.23(1H, dd, J=8.2, 6.7 Hz), 7.14 (2H, d, J=7.6 Hz), 7.02 (1H, dd, J=8.1,1.5 Hz), 6.57 (1H, d, J=3.2 Hz), 6.38 (1H, dd, J=3.2, 0.7 Hz), 5.23 (2H,s), 3.72 (3H, s), 3.15 (2H, t, J=7.9 Hz), 2.76 (2H, t, J=7.9 Hz), 2.28(6H, s).

(3) Synthesis of 3-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]propionic acid[56]

To a solution of the compound [56-2] obtained in the process (2) (75 mg)in methanol (3 mL) was added an aqueous solution of 1 N-sodium hydroxide(3 mL) at room temperature, and then the reaction mixture was stirred at60° C. for 18 hours. After cooling to room temperature, to the reactionmixture was added 1N-hydrochloric acid for acidification, and theprecipitated solid was filtered to give the titled compound (61 mg) as ared solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.56 (1H, d, J=8.3 Hz), 7.33 (1H, s), 7.22(1H, dd, J=8.1, 6.8 Hz), 7.12 (2H, d, J=7.6 Hz), 7.02 (1H, dd, J=8.1,1.5 Hz), 6.57 (1H, d, J=3.2 Hz), 6.37 (1H, dd, J=3.2, 0.7 Hz), 5.22 (2H,s), 3.15 (2H, t, J=7.9 Hz), 2.80 (2H, t, J=7.8 Hz), 2.26 (6H, s).

Example 57 Synthesis of3-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]-3-hydroxypropionic acid [57](hereinafter referred to as a compound [57])

(1) Synthesis of 1-(2,6-dimethylbenzyl)-1H-indole-6-carbaldehyde [57-1](hereinafter referred to as a compound [57-1])

To a solution of indole-6-carboxaldehyde (457 mg) inN,N-dimethylformamide (5 mL) were added potassium carbonate (936 mg) and2,6-dimethylbenzyl chloride (752 mg) at room temperature, and then thereaction mixture was subjected to microwave irradiation at 160° C. for30 minutes. The reaction mixture was quenched with water, and extractedwith ethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (740 mg) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 10.11 (1H, s), 8.08 (1H, s), 7.73 (1H, d,J=8.1 Hz), 7.68 (1H, dd, J=8.2, 1.3 Hz), 7.24 (1H, dd, J=7.4, 6.5 Hz),7.14 (2H, d, J=7.6 Hz), 6.83 (1H, d, J=3.2 Hz), 6.48 (1H, d, J=2.9 Hz),5.34 (2H, s), 2.27 (6H, s).

(2) Synthesis of ethyl3-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]-3-hydroxypropionate [57-2](hereinafter referred to as a compound [57-2])

To a solution of the compound [57-1] obtained in the process (1) (369mg) in benzene (10 mL) were added ethyl bromoacetate (0.25 mL) and zinc(193 mg) at room temperature, and then the reaction mixture was heatedat reflux for 1 hour. After cooling to room temperature, the insolublematerials were filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (475 mg) as a yellow liquid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.62-7.59 (2H, m), 7.22 (1H, dd, J=8.1, 6.8Hz) 7.13-7.11 (3H, m), 6.59 (1H, d, J=3.2 Hz), 6.38 (1H, dd, J=3.2, 0.7Hz), 5.35-5.31 (1H, m), 5.24 (2H, s), 4.22 (2H, q, J=7.1 Hz), 3.30 (1H,s), 2.92-2.80 (2H, m), 2.26 (6H, s), 1.29 (3H, t, J=7.2 Hz).

(3) Synthesis of3-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]-3-hydroxypropionic acid [57]

To a solution of the compound [57-2] obtained in the process (2) (84 mg)in methanol (1 mL) was added an aqueous solution of 1N-sodium hydroxide(1 mL) at room temperature, and then the reaction mixture was stirred at60° C. for 18 hours. After cooling to room temperature, to the reactionmixture was added 1N-hydrochloric acid for acidification, and theprecipitated solid was filtered to give the titled compound (70 mg) as awhite solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.62 (1H, d, J=8.1 Hz), 7.57 (1H, s), 7.22(1H, dd, J=8.1, 7.1 Hz), 7.15-7.11 (3H, m), 6.61 (1H, d, J=3.2 Hz), 6.39(1H, d, J=3.4 Hz), 5.36 (1H, dd, J=8.7, 3.5 Hz), 5.25 (2H, s), 2.98 (1H,dd, J=16.3, 9.3 Hz), 2.89 (1H, dd, J=16.5, 3.3 Hz), 2.26 (6H, s).

Example 58 Synthesis of6-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]hexanoic acid [58] (hereinafterreferred to as a compound [58])

(1) Synthesis of methyl 6-(1H-indole-6-yl)hexanoate [58-1] (hereinafterreferred to as a compound [58-1])

To a solution of 4-(carboxylbutyl)triphenylphosphonium bromide (1.1 g)in dimethyl sulfoxide (10 mL) was added sodium hydride (205 mg) at roomtemperature, and then the reaction mixture was stirred at roomtemperature for 10 minutes. Indole-6-carboxaldehyde (292 mg) was addedat room temperature, and then the reaction mixture was heated to 100° C.for 20 hours. After cooling to room temperature, to the reaction mixturewas added 1N-hydrochloric acid for acidification, and extracted withchloroform. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. To a solution of the obtained residue in N,N-dimethylformamide(10 mL) were added potassium carbonate (421 mg) and methyl iodide (0.5mL) at room temperature, and then the reaction mixture was stirred atroom temperature for 10 minutes. The reaction mixture was quenched withwater, and extracted with ethyl acetate. The obtained organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. To a solution of the obtainedresidue in methanol (3 mL) was added 5% palladium on carbon (184 mg),and the reaction mixture was stirred at room temperature for 1 hourunder hydrogen atmosphere. The palladium on carbon was separated byfiltration, and then the filtrate was concentrated under reducedpressure to give the titled compound (182 mg) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 8.07 (1H, s), 7.55 (1H, d, J=8.1 Hz), 7.19(1H, s), 7.16-7.15 (1H, m), 6.96 (1H, d, J=8.1 Hz), 6.51 (1H, s), 3.66(3H, s), 2.72 (2H, t, J=7.6 Hz), 2.31 (2H, t, J=7.6 Hz), 1.72-1.63 (4H,m), 1.42-1.35 (2H, m).

(2) Synthesis of methyl6-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]hexanoate [58-2] (hereinafterreferred to as a compound [58-2])

To a solution of the compound [58-2] obtained in the process (1) (177mg) in N,N-dimethylformamide (3 mL) were added potassium carbonate (258mg) and 2,6-dimethylbenzyl chloride (258 mg) at room temperature, andthen the reaction mixture was stirred at 130° C. for 5 hours. Aftercooling to room temperature, the reaction mixture was quenched withwater, and extracted with ethyl acetate. The obtained organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (171 mg)as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.53 (1H, d, J=8.1 Hz), 7.27 (1H, s),7.22-7.20 (1H, m), 7.11 (2H, d, J=7.3 Hz), 6.98 (1H, d, J=8.8 Hz), 6.53(1H, d, J=3.7 Hz), 6.35 (1H, d, J=3.4 Hz), 5.21 (2H, s), 3.67 (3H, s),2.78 (2H, t, J=7.7 Hz), 2.33 (2H, t, J=7.7 Hz), 2.26 (6H, s), 1.77-1.66(4H, m), 1.46-1.39 (2H, m).

(3) Synthesis of 6-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]hexanoic acid[58]

To a solution of the compound [58-2] obtained in the process (2) (169mg) in methanol (3 mL) was added an aqueous solution of 1N-sodiumhydroxide (3 mL) at room temperature, and then the reaction mixture wasstirred at 60° C. for 2 hours. After cooling to room temperature, thereaction mixture was quenched with 1N-hydrochloric acid foracidification, and the precipitated solid was filtered to give thetitled compound (120 mg) as a red solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.55 (1H, d, J=8.1 Hz), 7.28 (1H, s),7.24-7.20 (1H, m), 7.12 (2H, d, J=7.6 Hz), 6.99 (1H, dd, J=8.2, 1.3 Hz),6.55 (1H, d, J=3.2 Hz), 6.36 (1H, d, J=3.2 Hz), 5.22 (2H, s), 2.80 (2H,t, J=7.7 Hz), 2.38 (2H, t, J=7.4 Hz), 2.26 (6H, s), 1.79-1.68 (4H, m),1.50-1.42 (2H, m).

Example 59 Synthesis of4-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]-4-oxobutanoic acid [59](hereinafter referred to as a compound [59])

(1) Synthesis of 1-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]ethanone[59-1] (hereinafter referred to as a compound [59-1])

To a solution of the compound [57-1] obtained in the process (1) ofExample 57 (1.4 g) in tetrahydrofuran (10 mL) was added a 1M solution ofmethylmagnesium bromide in tetrahydrofuran (7 mL) at room temperature,and then the reaction mixture was stirred at room temperature for 10minutes. To the reaction mixture was added a saturated aqueous solutionof ammonium chloride, and extracted with chloroform. The obtainedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. To a solution of theobtained residue in acetone (20 mL) was added manganese dioxide (5.1 g),and the reaction mixture was stirred at room temperature for 2 days. Themanganese dioxide was filtered through a pad of celite, and then thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titledcompound (680 mg) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.20 (1H, d, J=3.7 Hz), 7.76 (1H, dd, J=8.3,1.5 Hz), 7.66 (1H, dd, J=8.3, 0.7 Hz), 7.25-7.21 (1H, m), 7.13 (2H, d,J=7.6 Hz), 6.78 (1H, d, J=2.9 Hz), 6.44 (1H, dd, J=3.2, 0.7 Hz), 5.32(2H, s), 2.70 (3H, s), 2.26 (6H, s).

(2) Synthesis of ethyl4-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]-4-oxobutanoate [59-2](hereinafter referred to as a compound [59-2])

The solution of the compound [59-1] obtained in the process (1) (103 mg)in tetrahydrofuran (3 mL) was cooled to 0° C. TO the solution was added1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.5mL) at 0° C. Then, the reaction mixture was stirred at 0° C. for 5minutes, and to the reaction mixture was added ethyl bromoacetate (0.1mL) at 0° C. and stirred for 30 minutes. The reaction mixture wasallowed to warm to room temperature, and stirred for 2 hours. To thereaction mixture was added a saturated aqueous solution of ammoniumchloride, and extracted with ethyl acetate. The obtained organic layerwas dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (55 mg)as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.23 (1H, s), 7.80 (1H, dd, J=8.4, 1.6 Hz),7.66 (1H, dd, J=8.3, 0.7 Hz), 7.26-7.21 (1H, m), 7.13 (2H, d, J=7.3 Hz),6.77 (1H, d, J=3.4 Hz), 6.44 (1H, dd, J=3.2, 0.7 Hz), 5.32 (2H, s), 4.19(2H, q, J=7.1 Hz), 3.45 (2H, t, J=6.8 Hz), 2.81 (2H, t, J=6.8 Hz), 2.26(6H, s), 1.29 (3H, t, J=7.2 Hz).

(3) Synthesis of 4-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]-4-oxobutanoicacid [59]

To a solution of the compound [59-2] obtained in the process (2) (496mg) in methanol (10 mL) was added an aqueous solution of 1N-sodiumhydroxide (10 mL), and the reaction mixture was stirred at 60° C. for 2hours. After cooling to room temperature, to the reaction mixture wasadded 1N-hydrochloric acid for acidification, and the precipitated solidwas filtered to give the titled compound (425 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 8.25 (1H, s), 7.76 (1H, dd, J=8.3, 1.5 Hz),7.63 (1H, d, J=8.3 Hz), 7.23-7.19 (1H, m), 7.13 (2H, d, J=7.6 Hz), 6.87(1H, d, J=3.2 Hz), 6.46 (1H, d, J=3.2 Hz), 5.44 (2H, d, J=2.0 Hz), 3.41(2H, t, J=6.3 Hz), 2.73 (2H, t, J=6.5 Hz), 2.26 (6H, s).

Example 60 Synthesis of4-[1-(2,6-dimethylbenzyl)-1H-indole-6-yl]butanoic acid [60] (hereinafterreferred to as a compound [60])

To an aqueous solution (2 mL) of zinc powder (1.2 g) was added mercurychloride (124 mg) at room temperature, and then the reaction mixture wasstirred at room temperature for 30 minutes. To the reaction mixture wereadded the compound [59] obtained in Example 59 (73 mg), toluene (1 mL),water (1 mL) and concentrated hydrochloric acid (1 mL) at roomtemperature, and then the reaction mixture was heated at reflux for 4hours. After cooling to room temperature, the reaction mixture wasquenched with water, and extracted with chloroform. The obtained organiclayer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titledcompound (35 mg) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.55 (1H, d, J=8.8 Hz), 7.28 (1H, s),7.23-7.19 (1H, m), 7.11 (2H, d, J=7.8 Hz), 6.99 (1H, d, J=7.8 Hz), 6.54(1H, d, J=3.2 Hz), 6.35 (1H, d, J=3.2 Hz), 5.21 (2H, s), 2.85 (2H, t,J=7.3 Hz), 2.44 (2H, t, J=7.3 Hz), 2.26 (6H, s), 2.11-2.03 (2H, m).

Example 61 Synthesis of1-(2,6-dimethylbenzyl)-3-methyl-1H-indole-6-carboxylic acid [61](hereinafter referred to as a compound [61])

(1) Synthesis of methyl1-(2,6-dimethylbenzyl)-3-methyl-1H-indole-6-carboxylate [61-1](hereinafter referred to as a compound [61-1])

To a solution of methyl 3-methyl-1H-indole-6-carboxylate (2.2 g)obtained by the method described in the document (WO 1998/15530 A) inN,N-dimethylformamide (20 mL) were added potassium carbonate (3.1 g) and2,6-dimethylbenzyl chloride (2.7 g) at room temperature, and then thereaction mixture was stirred at 130° C. for 5 hours. After cooling toroom temperature, the reaction mixture was quenched with water, andextracted with ethyl acetate. The obtained organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The obtained residue was purified byre-crystallization to give the titled compound (2.6 g) as a yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.24 (1H, dd, J=1.3, 0.6 Hz), 7.83 (1H, dd,J=8.3, 1.5 Hz), 7.58 (1H, dd, J=8.4, 0.6 Hz), 7.23 (1H, dd, J=8.3, 6.8Hz), 7.13 (2H, d, J=7.6 Hz), 6.51 (1H, s), 5.26 (2H, s), 3.97 (3H, s),2.26 (6H, s), 2.23 (3H, s).

(2) Synthesis of 1-(2,6-dimethylbenzyl)-3-methyl-1H-indole-6-carboxylicacid [61]

To a solution of the compound [61-1] obtained in the process (1) (77 mg)in methanol (1 mL) was added an aqueous solution of 1N-sodium hydroxide(1 mL) at room temperature, and then the reaction mixture was stirred at60° C. for 10 hours. After cooling to room temperature, to the reactionmixture was added 1N-hydrochloric acid for acidification, and theprecipitated solid was filtered to give the titled compound (73 mg) as ayellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.32 (1H, s), 7.91 (1H, dd, J=8.3, 1.5 Hz),7.62 (1H, d, J=8.5 Hz), 7.24-7.22 (1H, m), 7.14 (2H, d, J=7.6 Hz), 6.55(1H, d, J=1.0 Hz), 5.29 (2H, s), 5.28 (6H, s), 2.24 (3H, s).

ESI-MS found: 294 [M+H]⁺

Example 62 Synthesis of potassium1-(2,6-dimethylbenzyl)-3-methyl-1H-indole-6-carboxylate [62](hereinafter referred to as a compound [62])

To a solution of the compound [61] (2.1 g) in ethanol (20 mL) was addedan aqueous solution of 1N-potassium hydroxide (7.1 mL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (2.4 g) as a yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 8.19 (1H, s), 7.75 (1H, d, J=8.3, 1.5 Hz),7.45 (1H, dd, J=8.3, 0.7 Hz), 7.19-7.17 (1H, m), 7.10 (2H, d, J=7.6 Hz),6.40 (1H, s), 5.30 (2H, s), 2.24 (6H, s), 2.19 (3H, s).

ESI-MS found: 294 [M+K+2H]⁺

Example 63 Synthesis of[1-(2,6-dimethylbenzyl)-3-methyl-1H-indole-6-yl]methanol [63](hereinafter referred to as a compound [63])

To a solution of the compound [61-1] obtained in the process (1) ofExample 61 (265 mg) in tetrahydrofuran (10 mL) was added lithiumaluminum hydride (126 mg) at 0° C., and then the reaction mixture wasstirred at room temperature for 10 minutes. The reaction mixture wasquenched with water and 1N-hydrochloric acid, and then extracted withchloroform. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (179 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.56 (1H, d, J=7.8 Hz), 7.48 (1H, s),7.24-7.20 (1H, m), 7.15-7.11 (3H, m), 6.37 (1H, s), 5.19 (2H, s), 4.86(2H, d, J=5.6 Hz), 2.27 (6H, s), 2.22 (3H, s), 1.66 (1H, t, J=6.0 Hz).

Example 64 Synthesis of2-[1-(2,6-dimethylbenzyl)-3-methyl-1H-indole-6-yl]acetic acid [64](hereinafter referred to as a compound [64])

(1) Synthesis of (3-methyl-1-tosyl-1H-indole-6-yl)methanol [64-1](hereinafter referred to as a compound [64-1])

To a solution of methyl 3-methyl-1H-indole-6-carboxylate (1.3 g)obtained with the method described in the document (WO 1998/15530 A) in2-pentanone (40 mL) were added 4-methylbenzenesulfonyl chloride (2.0 g)and potassium carbonate (2.9 g) at room temperature, and then thereaction mixture was heated at reflux for 8 hours. After cooling to roomtemperature, the reaction mixture was quenched with water, and extractedwith ethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. To a solution of the obtained residue intetrahydrofuran (20 mL) was added a solution of lithium aluminum hydride(518 mg) in tetrahydrofuran (20 mL) at 0° C., and then the reactionmixture was stirred for 10 minutes. The reaction mixture was quenchedwith water and 1N-hydrochloric acid, and then extracted with chloroform.The obtained organic layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive the titled compound (1.6 g) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.98 (1H, s), 7.75 (2H, d, J=8.3 Hz), 7.44(1H, d, J=8.1 Hz), 7.31-7.26 (2H, m), 7.21 (2H, d, J=8.1 Hz), 4.81 (2H,d, J=5.1 Hz), 2.34 (3H, s), 2.24 (3H, s), 1.77 (1H, t, J=5.4 Hz).

(2) Synthesis of 2-(3-methyl-1-tosyl-1H-indole-6-yl)acetonitrile [64-2](hereinafter referred to as a compound [64-2])

The solution of the compound [64-1] obtained in the process (1) (1.6 g)in chloroform (12 mL) was cooled to 0° C., and to the solution wereadded triethylamine (0.97 mL) and methanesulfonyl chloride (0.54 mL) at0° C., and then the reaction mixture was stirred at 0° C. for 30minutes, and subsequently stirred at room temperature for 16 hours. Thereaction mixture was quenched with a saturated aqueous solution ofammonium chloride, and extracted with chloroform. The obtained organiclayer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. To a solution of theobtained residue in dimethyl sulfoxide (20 mL) was added sodium cyanide(516 mg) at room temperature, and then the reaction mixture was stirredat room temperature for 20 hours. The reaction mixture was quenched withwater, and extracted with chloroform. The obtained organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (1.3 g)as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.93 (1H, s), 7.74 (2H, d, J=8.5 Hz), 7.45(1H, d, J=8.1 Hz), 7.32 (1H, s), 7.23-7.21 (3H, m), 3.86 (2H, s), 2.34(3H, s), 2.24 (3H, s).

(3) Synthesis of methyl 2-(3-methyl-1H-indole-6-yl)acetate [64-3](hereinafter referred to as a compound [64-3])

To a solution of the compound [64-2] obtained in the process (2) (1.3 g)in ethanol (10 mL) was added an aqueous solution of 3N-sodium hydroxide(10 mL) at room temperature, and then the reaction mixture was heated atreflux for 20 hours. After cooling to room temperature, to the reactionmixture was added 1N-hydrochloric acid for acidification, and extractedwith chloroform. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. To a solution of the obtained residue inN,N-dimethylformamide (15 mL) were added potassium carbonate (846 mg)and methyl iodide (0.5 mL) at 0° C., and then the reaction mixture wasstirred at room temperature for 10 minutes. The reaction mixture wasquenched with water, and extracted with ethyl acetate. The obtainedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titledcompound (677 mg) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.89 (1H, s), 7.53 (1H, d, J=7.8 Hz), 7.28(1H, s), 7.05 (1H, d, J=8.1 Hz), 6.96 (1H, s), 3.74 (2H, s), 3.69 (3H,s), 2.33 (3H, s).

(4) Synthesis of methyl2-[1-(2,6-dimethylbenzyl)-3-methyl-1H-indole-6-yl]acetate [64-4](hereinafter referred to as a compound [64-4])

To a solution of the compound [64-3] obtained in the process (3) (677mg) in N,N-dimethylformamide (5 mL) were added potassium carbonate (936mg) and 2,6-dimethylbenzyl chloride (794 mg) at room temperature, andthen the reaction mixture was stirred at 130° C. for 8 hours. Aftercooling to room temperature, the reaction mixture was quenched withwater, and extracted with chloroform. The obtained organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (278 mg)as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.53 (1H, d, J=7.6 Hz), 7.38 (1H, s),7.24-7.21 (1H, m), 7.13 (2H, d, J=7.3 Hz), 7.07 (1H, d, J=7.6 Hz), 6.34(1H, s), 5.18 (2H, s), 3.81 (2H, s), 3.72 (3H, s), 2.27 (6H, s), 2.21(3H, s).

(5) Synthesis of2-[1-(2,6-dimethylbenzyl)-3-methyl-1H-indole-6-yl]acetic acid [64]

To a solution of the compound [64-4] obtained in the process (4) (268mg) in methanol (5 mL) was added an aqueous solution of 1N-sodiumhydroxide (5 mL) at room temperature, and then the reaction mixture wasstirred at 60° C. for 2 hours. After cooling to room temperature, to thereaction mixture was added 1N-hydrochloric acid for acidification, andthe precipitated solid was filtered to give the titled compound (226 mg)as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.53 (1H, d, J=8.1 Hz), 7.37 (1H, s),7.24-7.20 (1H, m), 7.12 (2H, d, J=8.1 Hz), 7.07 (1H, d, J=8.1 Hz), 6.34(1H, s), 5.17 (2H, s), 3.82 (2H, s), 2.26 (6H, s), 2.20 (3H, s). ESI-MSfound: 308 [M+H]⁺

Example 65 Synthesis of potassium2-[1-(2,6-dimethylbenzyl)-3-methyl-1H-indole-6-yl]acetate [65](hereinafter referred to as a compound [65])

To a solution of the compound [64] (226 mg) in ethanol (5 mL) was addedan aqueous solution of 1N-potassium hydroxide (0.74 mL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (254 mg) as a yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.46 (1H, s), 7.37 (1H, d, J=8.1 Hz)7.19-7.15 (1H, m), 7.09 (2H, d, J=7.6 Hz), 7.06 (1H, dd, J=8.1, 1.5 Hz),6.23-6.22 (1H, m), 5.22 (2H, s), 3.61 (2H, s), 2.23 (6H, s), 2.15 (3H,s).

ESI-MS found: 308 [M+K+2H]⁺

Example 66 Synthesis of2-[1-(2,6-dimethylbenzyl)-3-methyl-1H-indazole-6-yl]acetic acid [66](hereinafter referred to as a compound [66])

(1) Synthesis of 6-bromo-1-(2,6-dimethylbenzyl)-3-methyl-1H-indazole[66-1] (hereinafter referred to as a compound [66-1])

To a solution of 6-bromo-3-methyl-1H-indazole (467 mg) obtained with themethod described in the document (JP 2009-528363 W) inN,N-dimethylformamide (10 mL) were added potassium carbonate (618 mg)and 2,6-dimethylbenzyl chloride (518 mg) at room temperature, and thenthe reaction mixture was stirred at room temperature for 20 hours. Thereaction mixture was quenched with water, and extracted with ethylacetate. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (555 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.47 (1H, d, J=8.8 Hz), 7.22-7.14 (2H, m),7.11-7.09 (3H, m), 5.45 (2H, s), 2.51 (3H, s), 2.33 (6H, s).

(2) Synthesis of 6-allyl-1-(2,6-dimethylbenzyl)-3-methyl-1H-indazole[66-2] (hereinafter referred to as a compound [66-2])

To a solution of the compound [66-1] obtained in the process (1) (98 mg)in N,N-dimethylformamide (3 mL) were added allyltributyl tin (0.3 mL),lithium chloride (41 mg) andbis(triphenylphosphine)palladium(II)dichloride (21 mg) at roomtemperature, and then the reaction mixture was stirred at 120° C. for 2hours. After cooling to room temperature, the reaction mixture wasquenched with water, and extracted with ethyl acetate. The obtainedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titledcompound (86 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.52 (1H, d, J=7.8 Hz), 7.18-7.15 (1H, m),7.07 (2H, d, J=7.3 Hz), 6.91 (1H, dd, J=8.3, 1.2 Hz), 6.75 (1H, s),5.96-5.85 (1H, m), 5.47 (2H, s), 5.07-5.02 (2H, m), 3.40 (2H, d, J=6.6Hz), 2.52 (3H, s), 2.33 (6H, s).

(3) Synthesis of2-[1-(2,6-dimethylbenzyl)-3-methyl-1H-indazole-6-yl]acetaldehyde [66-3](hereinafter referred to as a compound [66-3])

The solution of the compound [66-2] obtained in the process (2) (432 mg)in tert-butanol (10 mL) and water (5 mL) was cooled to 0° C. To thesolution were added sodium periodate (1.3 g) and an aqueous solution of4% osmium tetraoxide (0.3 mL) at 0° C. The reaction mixture was stirredat 0° C. for 30 minutes, and then stirred at room temperature for 4hours. The reaction mixture was quenched with water, and extracted withchloroform. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (152 mg) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 9.68 (1H, t, J=2.4 Hz), 7.60 (1H, d, J=7.8Hz) 7.20-7.16 (1H, m), 7.08 (2H, d, J=7.8 Hz), 6.90 (1H, d, J=8.3 Hz),6.74 (1H, s), 5.49 (2H, s), 3.68 (2H, d, J=2.0 Hz), 2.53 (3H, s), 2.32(6H, s).

(4) Synthesis of2-[1-(2,6-dimethylbenzyl)-3-methyl-1H-indazole-6-yl]acetic acid [66]

To a solution of the compound [66-3] obtained in the process (3) (149mg) in tert-butanol (10 mL) and water (5 mL) were added2-methyl-2-butene (0.25 mL), sodium dihydrogen phosphate 2 hydrate (86mg) and sodium chlorite (175 mg) at room temperature, and the reactionmixture was stirred at room temperature for 1 hour. To the reactionmixture was added hydrochloric acid, and extracted with chloroform. Theobtained organic layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive the titled compound (126 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.58 (1H, d, J=8.3 Hz), 7.18-7.15 (1H, m),7.07 (2H, d, J=7.3 Hz), 7.00 (1H, dd, J=8.3, 1.5 Hz), 6.88 (1H, s), 5.49(2H, s), 3.68 (2H, s), 2.53 (3H, s), 2.33 (6H, s).

ESI-MS found: 309 [M+H]⁺

Example 67 Synthesis of 2-(1-benzyl-3-chloro-1H-indole-6-yl)acetic acid[67] (hereinafter referred to as a compound [67])

To a solution of the compound [4] obtained in Example 4 (82 mg) intetrahydrofuran (1 mL) was added N-chlorosuccinimide (26 mg) at roomtemperature, and then the reaction mixture was stirred at roomtemperature for 1 hour. To the reaction mixture was added4N-hydrochloric acid for acidification, and then extracted with ethylacetate. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (19 mg) as a red solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.47 (1H, d, J=8.3 Hz), 7.31-7.22 (5H, m),7.18-7.12 (2H, m), 7.07 (1H, dd, J=8.2, 1.1 Hz), 5.33 (2H, s), 3.66 (2H,s).

ESI-MS found: 300 [M+H]⁺

Example 68 Synthesis of2-[3-chloro-1-(2,6-dimethylbenzyl)-1H-indole-6-yl]acetic acid [68](hereinafter referred to as a compound [68])

The titled compound (43 mg) as a white solid was prepared from thecompound [5] obtained in Example 5 (80.8 mg) and N-chlorosuccinimide(42.9 mg) according to the method of Example 67.

¹H-NMR (400 MHz, CD₃OD) δ: 7.51 (1H, s), 7.46 (1H, d, J=8.1 Hz), 7.21(1H, t, J=7.7 Hz), 7.17-7.08 (3H, m), 6.51 (1H, s), 5.30 (2H, s), 3.74(2H, s), 2.25 (6H, s).

ESI-MS found: 328 [M+H]⁺

Example 69 Synthesis of1-(2,6-dimethylbenzyl)-2-methyl-1H-indole-6-carboxylic acid [69](hereinafter referred to as a compound [69])

(1) Synthesis of methyl 4-methyl-3-nitrobenzoate [69-1] (hereinafterreferred to as a compound [69-1])

To a solution of 4-Methyl-3-nitrobenzoic acid (25.4 g) in methanol (300mL) was slowly added concentrated sulfuric acid (2 mL), and then thereaction mixture was heated at reflux for 16 hours. The reaction mixturewas concentrated under reduced pressure, and then the reaction mixturewas neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The obtained organic layerwas dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure to give the titled compound (26.9 g)as a pale yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.62 (1H, s), 8.15 (1H, dd, J=7.8, 1.2 Hz),7.45 (1H, d, J=7.8 Hz), 3.96 (3H, s), 2.67 (3H, s).

(2) Synthesis of methyl 3-nitro-4-(2-oxopropyl)benzoate [69-2](hereinafter referred to as a compound [69-2])

To a solution of the compound [69-1] obtained in the process (1) (693mg) in N,N-dimethylformamide (3.5 mL) was added N,N-dimethylformamidedimethyl acetal (1.5 mL) at room temperature, and then the reactionmixture was subjected to microwave irradiation at 160° C. for 20minutes. The reaction mixture was concentrated under reduced pressure togive a reddish brown solid. To a solution of the obtained solid inchloroform (6 mL) were added pyridine (0.46 mL) and acetyl chloride(0.36 mL) at room temperature, and then the reaction mixture was stirredat room temperature for 3 days. The reaction mixture was quenched withwater, and concentrated under reduced pressure. To the obtained residuewere added 1,4-dioxane (3 mL) and water (1.5 mL), and then the reactionmixture was stirred at 100° C. for 18 hours. The reaction mixture wasconcentrated under reduced pressure, and then quenched with water, andextracted with ethyl acetate. The obtained organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography to give the titled compound (589 mg) as a brownoil.

¹H-NMR (400 MHz, CDCl₃) δ: 8.75 (1H, d, J=1.2 Hz), 8.24 (1H, dd, J=7.8,2.0 Hz), 7.38 (1H, d, J=7.8 Hz), 4.20 (2H, s), 3.97 (3H, s), 2.35 (3H,s).

(3) Synthesis of methyl 2-methyl-1H-indole-6-carboxylate [69-3](hereinafter referred to as a compound [69-3])

To a solution of the compound [69-2] obtained in the process (2) (589mg) in acetic acid (5 mL) were added iron powder (691 mg), and then thereaction mixture was stirred at 100° C. for 8 hours. After cooling toroom temperature, the insoluble materials were filtered, and thefiltrate was concentrated under reduced pressure. The residue was addedwater, and extracted with ethyl acetate. The obtained organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (303 mg)as a brown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.21-8.20 (1H, br), 8.04 (1H, s), 7.77 (1H,dd, J=8.5, 1.5 Hz), 7.51 (1H, d, J=8.3 Hz), 6.28-6.27 (1H, m), 3.92 (3H,s), 2.49 (3H, s).

(4) Synthesis of 1-(2,6-dimethylbenzyl)-2-methyl-1H-indole-6-carboxylicacid [69]

The titled compound (19 mg) as a brown solid was prepared from thecompound [69-3] obtained in the process (3) (70 mg) and2,6-dimethylbenzyl chloride (69 mg) according to the method of theprocess (7) of Example 4.

¹H-NMR (400 MHz, DMSO-d₆) δ: 7.74 (1H, s), 7.54 (1H, d, J=8.3 Hz), 7.46(1H, d, J=8.3 Hz), 7.15-7.10 (1H, m), 7.04 (2H, d, J=7.8 Hz), 6.33 (1H,s), 5.45 (2H, s), 2.28 (3H, s), 2.08 (6H, s).

ESI-MS found: 294 [M+H]⁺

Example 70 Synthesis of 1-benzyl-2-methyl-1H-indole-6-carboxylic acid[70] (hereinafter referred to as a compound [70])

The titled compound (68 mg) as a white solid was prepared from thecompound [69-3] obtained in the process (3) of Example 69 (70 mg) andbenzyl chloride (63 μL) according to the method of the process (7) ofExample 4.

¹H-NMR (400 MHz, CD₃OD) δ: 7.98 (1H, s), 7.70 (1H, dd, J=8.3, 1.2 Hz),7.51 (1H, d, J=8.3 Hz), 7.29-7.19 (3H, m), 6.96 (2H, d, J=7.3 Hz), 6.38(1H, s), 5.47 (2H, s), 2.38 (3H, s).

ESI-MS found: 266 [M+H]⁺

Example 71 Synthesis of2-methyl-1-(2-methylbenzyl)-1H-indole-6-carboxylic acid [71](hereinafter referred to as a compound [71])

The titled compound (63 mg) as a white solid was prepared from thecompound [69-3] obtained in the process (3) of Example 69 (72 mg) and2-methylbenzyl chloride (73 μL) according to the method of the process(7) of Example 4.

¹H-NMR (400 MHz, CD₃OD) δ: 7.86 (1H, s), 7.71 (1H, dd, J=8.5, 1.2 Hz),7.53 (1H, d, J=7.6 Hz), 7.22 (1H, d, J=7.3 Hz), 7.11 (1H, t, J=7.6 Hz),6.93 (1H, t, J=7.6 Hz), 6.42 (1H, s), 6.05 (1H, d, J=7.3 Hz), 5.39 (2H,s), 2.45 (3H, s), 2.35 (3H, s).

ESI-MS found: 280 [M+H]⁺

Example 72 Synthesis of1-(2-chlorobenzyl)-2-methyl-1H-indole-6-carboxylic acid [72](hereinafter referred to as a compound [72])

The titled compound (71 mg) as a white solid was prepared from thecompound [69-3] obtained in the process (3) of Example 69 (72 mg) and2-chlorobenzyl chloride (72 μL) according to the method of the process(7) of Example 4.

¹H-NMR (400 MHz, CD₃OD) δ: 7.87 (1H, s), 7.72 (1H, d, J=7.8 Hz), 7.54(1H, d, J=7.8 Hz), 7.47 (1H, d, J=7.1 Hz), 7.24 (1H, t, J=7.6 Hz), 7.08(1H, t, J=6.8 Hz), 6.44 (1H, s), 6.18 (1H, d, J=6.8 Hz), 5.51 (2H, s),2.38 (3H, s).

ESI-MS found: 300 [M+H]⁺

Example 73 Synthesis of1-(2,6-dimethylbenzyl)-2-(trifluoromethyl)-1H-benzimidazole-6-carboxylicacid [73] (hereinafter referred to as a compound [73])

(1) Synthesis of methyl 3-nitro-4-(2,2,2-trifluoroacetamido)benzoate[73-1] (hereinafter referred to as a compound [73-1])

Methyl 4-aminobenzoate (1.0 g) was dissolved in trifluoroacetic acidanhydride (13 mL). Potassium nitrate (736 mg) was added at 0° C., andthen the reaction mixture was stirred at room temperature for 15 hours.The reaction mixture was quenched with water, and extracted with ethylacetate. The obtained organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure to give the titled compound (1.9 g) as a palebrown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 11.58 (1H, s), 8.99 (1H, d, J=2.0 Hz), 8.87(1H, d, J=8.8 Hz), 8.40 (1H, dd, J=8.8, 2.0 Hz), 4.00 (3H, s).

ESI-MS found: 291 [M−H]⁻

(2) Synthesis of methyl1-(2,6-dimethylbenzyl)-2-(trifluoromethyl)-3H-benzimidazole-6-carboxylate[73-2A] (hereinafter referred to as a compound [73-2A]) and methyl1-(2,6-dimethylbenzyl)-2-(trifluoromethyl)-1H-benzimidazole-5-carboxylate[73-2B] (hereinafter referred to as a compound [73-2B])

To a solution of the compound [73-1] obtained in the process (1) (616mg) in ethanol (14 mL) were added water (7 mL), iron powder (453 mg) andammonium chloride (857 mg), and then the reaction mixture was heated atreflux for 4 hours. The insoluble materials were filtered through a padof celite, and the pad was washed with water and ethyl acetate. Theorganic layer was separated from the filtrate and washed with brine,dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give a benzoimidazole (225 mg) asa yellow solid. The obtained benzoimidazole (105 mg) was dissolved inN-methyl-2-pyrrolidone (2.3 mL). Potassium carbonate (227 mg) and2,6-dimethylbenzyl chloride (139 mg) were added, and then the reactionmixture was subjected to microwave irradiation at 160° C. for 30minutes. The reaction mixture was quenched with water, and extractedwith ethyl acetate. The obtained organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give a mixture of the titledcompounds [73-2A] and [73-2B] in 118 mg (79%) as a yellow solid.

ESI-MS found: 363 [M+H]⁺

(3) Synthesis of1-(2,6-dimethylbenzyl)-2-(trifluoromethyl)-1H-benzimidazole-6-carboxylicacid [73]

To a solution of the mixture of the compounds [73-2A] and [73-2B]obtained in the process (2) (118 mg) in tetrahydrofuran (3.3 mL) wasadded 1N-sodium hydroxide (1.7 mL), and then the reaction mixture wassubjected to microwave irradiation at 120° C. for 20 minutes. Thereaction mixture was added 1N-hydrochloric acid, and extracted withethyl acetate. The obtained organic layer was washed with brine, driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby COOH column chromatography to give the titled compound (13 mg) as apale yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.97 (1H, dd, J=8.5, 1.5 Hz), 7.85 (1H, d,J=8.5 Hz), 7.29-7.23 (2H, m), 7.15 (2H, d, J=7.6 Hz), 5.64 (2H, s), 2.25(6H, s).

ESI-MS found: 349 [M+H]⁺

Example 74 Synthesis of potassium2-(1-benzyl-2,3-dihydro-1H-indole-6-yl)acetate [74] (hereinafterreferred to as a compound [74])

(1) Synthesis of tert-butyl 6-allyl-2,3-dihydro-1H-indole-1-carboxylate[74-1] (hereinafter referred to as a compound [74-1])

The titled compound (5.7 g) as a colorless oil was prepared fromtert-butyl 6-bromo-2,3-dihydro-1H-indole-1-carboxylate (7.5 g) obtainedwith the method described in the document (WO 1998/43956 A) according tothe method of the process (2) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.72 (1H, brs), 7.05 (1H, d, J=7.4 Hz), 6.76(1H, d, J=7.4 Hz), 6.02-5.89 (1H, m), 5.16-4.98 (2H, m), 4.03-3.91 (2H,m), 3.36 (2H, d, J=6.6 Hz), 3.04 (2H, t, J=8.5 Hz), 1.56 (9H, brs).

ESI-MS found: 204 [M-tBu+H]⁺

(2) Synthesis of tert-butyl2,3-dihydro-6-(2-oxoethyl)-1H-indole-1-carboxylate [74-2] (hereinafterreferred to as a compound [74-2])

The titled compound (3.8 g) as a colorless oil was prepared from thecompound [74-1] obtained in the process (1) (5.9 g) according to themethod of the process (3) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 9.73 (1H, t, J=2.0 Hz), 7.78 (1H, brs), 7.13(1H, d, J=7.4 Hz), 6.76 (1H, d, J=7.4 Hz), 3.99 (2H, t, J=8.7 Hz), 3.64(2H, d, J=2.0 Hz), 3.08 (2H, t, J=8.7 Hz), 1.56 (9H, brs).

ESI-MS found: 206 [M-tBu+H]⁺

(3) Synthesis of methyl 2-(2,3-dihydro-1H-indole-6-yl)acetate [74-3A](hereinafter referred to as a compound [74-3A]) and methyl2-(5-chloro-2,3-dihydro-1H-indole-6-yl)acetate [74-3B] (hereinafterreferred to as a compound [74-3B])

To a solution of the compound [74-2] obtained in the process (2) (3.8 g)in tert-butanol (144 mL) were added water (36 mL), sodium dihydrogenphosphate 2 hydrate (2.3 g), 2-methyl-2-butene (4.6 g) and sodiumchlorite (3.7 g), and the reaction mixture was stirred for 2 hours on anice bath. The reaction mixture was quenched with water and 1N-hydrochloric acid, and extracted with ethyl acetate. The obtainedorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure to give a crude carboxylate (3.8 g) as a colorless foamysubstance.

The obtained crude carboxylate (3.8 g) was dissolved inN,N-dimethylformamide (70 mL). Sodium hydrogen carbonate (2.3 g) andmethyl iodide (4.2 mL) were added, and then the reaction mixture wasstirred at 60° C. for 2 hours. The reaction mixture was quenched withwater, and extracted with ethyl acetate. The obtained organic layer waswashed with brine, dried over anhydrous sodium sulfate, filtered, andthe filtrate was concentrated under reduced pressure to give a crudeester as a pale brown oil.

The obtained crude ester was dissolved in chloroform (80 mL).Trifluoroacetic acid (80 mL) was added at room temperature, and then thereaction mixture was stirred at room temperature for 2 hours. Themixture was concentrated under reduced pressure, and then the reactionmixture was added an aqueous solution of sodium hydrogen carbonate, andextracted with ethyl acetate. The obtained organic layer was washed withbrine, dried over anhydrous sodium sulfate, filtered, and the filtratewas concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography to give the titled compound[74-3A] (0.8 g) as a brown solid. The titled compound [74-3B] (0.8 g) asa brown solid was also obtained.

[74-3A]

¹H-NMR (400 MHz, CDCl₃) δ: 7.05 (1H, d, J=7.4 Hz), 6.59 (1H, d, J=7.4Hz), 6.57 (1H, s), 3.68 (3H, s), 3.56 (2H, t, J=8.4 Hz), 3.52 (2H, s),3.00 (2H, t, J=8.4 Hz).

ESI-MS found: 192 [M-Boc+H]⁺

[74-3B]

¹H-NMR (400 MHz, CDCl₃) δ: 7.09 (1H, s), 6.54 (1H, s), 3.71 (3H, s),3.67 (2H, s), 3.57 (2H, t, J=8.4 Hz), 3.00 (2H, t, J=8.4 Hz).

ESI-MS found: 226 [M-Boc+H]⁺

(4) Synthesis of methyl 2-(1-benzyl-2,3-dihydro-1H-indole-6-yl)acetate[74-4] (hereinafter referred to as a compound [74-4])

To a solution of the compound [74-3A] obtained in the process (3) (30mg) in N,N-dimethylformamide (1.6 mL) were added cesium carbonate (163mg) and benzyl bromide (37 mL) at room temperature, and then thereaction mixture was subjected to microwave irradiation at 90° C. for 30minutes. The reaction mixture was quenched with water, and extractedwith ethyl acetate. The obtained organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (30 mg)as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.37-7.27 (5H, m), 7.03 (1H, d, J=7.3 Hz),6.57 (1H, dd, J=7.3, 1.0 Hz), 6.44 (1H, d, J=1.0 Hz), 4.26 (2H, s), 3.67(3H, s), 3.53 (2H, s), 3.31 (2H, t, J=8.4 Hz), 2.94 (2H, t, J=8.4 Hz).

ESI-MS found: 282 [M+H]⁺

(5) Synthesis of potassium2-(1-benzyl-2,3-dihydro-1H-indole-6-yl)acetate [74]

To a solution of the compound [74-4] obtained in the process (4) (30 mg)in tetrahydrofuran (1 mL) was added 1N-sodium hydroxide (0.5 mL), andthen the reaction mixture was stirred at room temperature for 24 hours.The reaction mixture was added 1N-hydrochloric acid, and extracted withethyl acetate. The obtained organic layer was washed with brine, driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was dissolvedin methanol and 1 M potassium hydroxide-methanol solution (92.4 μL) wasadded, and the solvent was concentrated under reduced pressure. Theobtained residue was suspended in ethyl acetate, and the solid wasfiltered to give the titled compound (23 mg) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 7.37-7.22 (5H, m), 6.85 (1H, d, J=7.3 Hz),6.47 (1H, d, J=1.2 Hz), 6.42 (1H, dd, J=7.3, 1.2 Hz), 4.19 (2H, s), 3.15(2H, t, J=8.3 Hz), 3.00 (2H, s), 2.79 (2H, t, J=8.3 Hz).

ESI-MS found: 268 [M+K+2H]⁺

Example 75 Synthesis of2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-1H-indole-6-yl]acetic acid [75](hereinafter referred to as a compound [75])

(1) Synthesis of methyl2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-1H-indole-6-yl]acetate [75-1](hereinafter referred to as a compound [75-1])

To a solution of the compound [74-3A] obtained in the process (3) ofExample 74 (0.7 g) in N,N-dimethylformamide (18 mL) were added potassiumcarbonate (1.5 g) and 2,6-dimethylbenzyl chloride (1.2 g) at roomtemperature. Then, the reaction mixture was subjected to microwaveirradiation at 90° C. for 30 minutes, and subsequently at 100° C. for 15minutes. The reaction mixture was quenched with water, and extractedwith ethyl acetate. The obtained organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (1.0 g)as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.12 (1H, dd, J=8.4, 6.5 Hz), 7.06-7.00 (3H,m), 6.57 (1H, dd, J=7.4, 1.1 Hz), 6.53 (1H, d, J=1.1 Hz), 4.21 (2H, s),3.71 (3H, s), 3.59 (2H, s), 3.11 (2H, t, J=8.3 Hz), 2.82 (2H, t, J=8.3Hz), 2.38 (6H, s).

ESI-MS found: 310 [M+H]⁺

(2) Synthesis of2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-1H-indole-6-yl]acetic acid [75]

To a solution of the compound [75-1] obtained in the process (1) (35 mg)in tetrahydrofuran (1 mL) was added 1N-sodium hydroxide (0.6 mL), andthen the reaction mixture was stirred at room temperature for 24 hours.Then, the reaction mixture was added 1N-hydrochloric acid, and extractedwith ethyl acetate. The obtained organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure to give the titled compound (33 mg)as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.11 (1H, dd, J=8.5, 6.7 Hz), 7.07-7.01 (3H,m), 6.58 (1H, dd, J=6.7, 1.2 Hz), 6.52 (1H, d, J=1.2 Hz), 4.21 (2H, s),3.62 (2H, s), 3.11 (2H, t, J=8.2 Hz), 2.82 (2H, t, J=8.2 Hz), 2.38 (6H,s).

ESI-MS found: 296 [M+H]⁺

Example 76 Synthesis of potassium2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-1H-indole-6-yl]acetate [76](hereinafter referred to as a compound [76])

To a solution of the compound [75-1] obtained in the process (1) ofExample 75 (1.1 g) in tetrahydrofuran (35 mL) was added 1N-sodiumhydroxide (19 mL), and then the reaction mixture was stirred at roomtemperature for 24 hours. The reaction mixture was added 1N-hydrochloricacid, and extracted with ethyl acetate. The obtained organic layer waswashed with brine, dried over anhydrous sodium sulfate, filtered, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was dissolved in methanol and 1 M potassium hydroxide-methanolsolution (3.48 mL) was added, and the solvent was concentrated underreduced pressure. The obtained residue was suspended in ethyl acetate,and the solid was filtered to give the titled compound (1.0 g) as awhite solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 7.12-7.01 (3H, m), 6.89 (1H, d, J=7.2 Hz),6.60 (1H, s), 6.46 (1H, d, J=7.2 Hz), 4.14 (2H, s), 3.25 (2H, s), 2.98(2H, t, J=8.2 Hz), 2.71 (2H, t, J=8.2 Hz), 2.34 (6H, s).

ESI-MS found: 296 [M+K+2H]⁺

Example 77 Synthesis of2-[5-chloro-1-(2,6-dimethylbenzyl)-2,3-dihydro-1H-indole-6-yl]aceticacid [77] (hereinafter referred to as a compound [77])

(1) Synthesis of methyl2-[5-chloro-1-(2,6-dimethylbenzyl)-2,3-dihydro-1H-indole-6-yl]acetate[77-1] (hereinafter referred to as a compound [77-1])

The titled compound (57 mg) as a white solid was prepared from thecompound [74-3B] obtained in the process (3) of Example 74 (43 mg) inN,N-dimethylformamide (1.8 mL), potassium carbonate (123 mg) and2,6-dimethylbenzyl chloride (65 mg) according to the method of theprocess (1) of Example 75.

¹H-NMR (400 MHz, CDCl₃) δ: 7.12 (1H, dd, J=8.3, 6.6 Hz), 7.05-7.04 (3H,m), 6.46 (1H, s), 4.18 (2H, s), 3.73 (3H, s), 3.72 (2H, s), 3.11 (2H, t,J=8.1 Hz), 2.82 (2H, t, J=8.1 Hz), 2.37 (6H, s).

ESI-MS found: 344 [M+H]⁺

(2) Synthesis of2-[5-chloro-1-(2,6-dimethylbenzyl)-2,3-dihydro-1H-indole-6-yl]aceticacid [77]

To a solution of the compound [77-1] obtained in the process (1) (57 mg)in tetrahydrofuran (1.6 mL) was added 1N-sodium hydroxide (0.9 mL), andthen the reaction mixture was stirred at room temperature for 20 hours.The reaction mixture was added 1N-hydrochloric acid, and extracted withethyl acetate. The obtained organic layer was washed with brine, driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure to give the titled compound (35 mg)as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 7.12 (1H, dd, J=8.3, 6.6 Hz), 7.07-7.02(3H, m), 6.45 (1H, s), 4.18 (2H, s), 3.77 (2H, s), 3.12 (2H, t, J=8.3Hz), 2.82 (2H, t, J=8.3 Hz), 2.37 (6H, s).

ESI-MS found: 330 [M+H]⁺

Example 78 Synthesis of(3-RS)-2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3-methyl-1H-indole-6-yl]aceticacid [78] (hereinafter referred to as a compound [78])

(1) Synthesis of (3-RS)-6-bromo-2,3-dihydro-3-methyl-1H-indole-2-one[78-1] (hereinafter referred to as a compound [78-1])

Sodium hydride (3.9 g) was suspended in dimethyl sulfoxide (24 mL), anddiethyl methyl malonate (16 mL) was added at 0° C., and then thereaction mixture was stirred at room temperature for 1.5 hours. Thereaction mixture was heated to 100° C., and a solution of2,5-dibromonitrobenzene (15.3 g) in dimethyl sulfoxide (17 mL) was addedat 100° C., and then the reaction mixture was stirred at 100° C. for 5hours. The reaction mixture was quenched with water, and extracted withethyl acetate. The obtained organic layer was washed with brine, driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved inethanol (75 mL), and tin (11.5 g) was added at room temperature.Concentrated hydrochloric acid (45 mL) was added at 0° C., and then thereaction mixture was heated at reflux for 2 hours. After cooling to roomtemperature, the reaction mixture was quenched with water, and extractedwith ethyl acetate. The obtained organic layer was washed with asaturated aqueous solution of sodium hydrogen carbonate and brine, driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (4.9 g)as a brown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.48 (1H, brs), 7.17 (1H, dd, J=7.9, 1.3 Hz),7.08 (1H, d, J=7.9 Hz), 7.07 (1H, s), 3.41 (1H, q, J=7.8 Hz), 1.48 (3H,d, J=7.8 Hz).

ESI-MS found: 226 [M+H]⁺

(2) Synthesis oftert-butyl(3-RS)-6-bromo-2,3-dihydro-3-methyl-1H-indole-1-carboxylate[78-2] (hereinafter referred to as a compound [78-2])

The compound [78-1] obtained in the process (1) (4.9 g) was suspended intoluene (22 mL), and borane dimethyl sulfide complex (4.4 mL) was addedat 0° C., and then the reaction mixture was heated at reflux for 2hours. The reaction mixture was cooled with ice-water bath, and anaqueous solution of 5N-sodium hydroxide (8 mL), an aqueous solution of8N-sodium hydroxide (8 mL) and ethyl acetate (8 mL) were added,successively, and then the reaction mixture was stirred at roomtemperature for 2.5 hours. The reaction mixture was quenched with water,and extracted with ethyl acetate. The obtained organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The residue wasdissolved in tetrahydrofuran (100 mL), and triethylamine (4.55 mL) and asolution of di-tert-butyl dicarbonate (6.2 g) in tetrahydrofuran (10 mL)were added successively at room temperature, and then a grain ofdimethylaminopyridine was added, and the reaction mixture was stirred atroom temperature for 22 hours. The reaction mixture was quenched withwater, and extracted with ethyl acetate. The obtained organic layer waswashed with brine, dried over anhydrous sodium sulfate, filtered, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography to give thetitled compound (4.6 g) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 8.03 (1H, s), 7.07 (1H, dd, J=7.9, 1.6 Hz),6.96 (1H, d, J=8.3 Hz), 4.19-4.08 (1H, m), 3.57-3.43 (1H, m), 3.39-3.27(1H, m), 1.53 (9H, brs), 1.30 (3H, d, J=6.8 Hz).

ESI-MS found: 256 [M-tBu+H]⁺

(3) Synthesis ofmethyl(3-RS)-2-(2,3-dihydro-3-methyl-1H-indole-6-yl)acetate [78-3](hereinafter referred to as a compound [78-3])

The titled compound (134 mg) as a colorless oil was prepared from thecompound [78-2] obtained in the process (2) (4.6 g) according to themethods of the processes (1) to (3) of Example 74.

¹H-NMR (400 MHz, CDCl₃) δ: 7.01 (1H, d, J=7.3 Hz), 6.62 (1H, d, J=7.3Hz), 6.57 (1H, s), 3.73-3.64 (2H, m), 3.68 (3H, s), 3.53 (2H, s),3.39-3.27 (1H, m), 3.11 (1H, t, J=8.7 Hz), 1.30 (3H, d, J=6.8 Hz).

ESI-MS found: 206 [M+H]⁺

(4) Synthesis ofmethyl(3-RS)-2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3-methyl-1H-indole-6-yl]acetate[78-4] (hereinafter referred to as a compound [78-4])

The titled compound (46 mg) as a colorless oil was prepared from thecompound [78-3] obtained in the process (3) (40 mg) and2,6-dimethylbenzyl chloride according to the method of the process (1)of Example 75.

¹H-NMR (400 MHz, CDCl₃) δ: 7.12 (1H, dd, J=8.3, 6.6 Hz), 7.07-7.02 (2H,m), 6.99 (1H, d, J=7.3 Hz), 6.60 (1H, d, J=7.3 Hz), 6.52 (1H, s), 4.30(1H, d, J=12.9 Hz), 4.10 (1H, d, J=12.9 Hz), 3.71 (3H, s), 3.59 (2H, s),3.24 (1H, t, J=8.4 Hz), 3.13 (1H, tq, J=8.3, 6.6 Hz), 2.67 (1H, t, J=8.2Hz), 2.38 (6H, s), 1.21 (3H, d, J=6.6 Hz).

ESI-MS found: 324 [M+H]⁺

(5) Synthesis of(3-RS)-2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3-methyl-1H-indole-6-yl]aceticacid [78]

The titled compound (26 mg) as a white solid was prepared from thecompound [78-4] obtained in the process (4) (46 mg) according to themethod of the process (2) of Example 77.

¹H-NMR (400 MHz, CDCl₃) δ: 7.12 (1H, dd, J=8.2, 6.5 Hz), 7.07-7.02 (2H,m), 7.00 (1H, d, J=7.3 Hz), 6.61 (1H, d, J=7.3 Hz), 6.51 (1H, s), 4.30(1H, d, J=12.9 Hz), 4.10 (1H, d, J=12.9 Hz), 3.62 (2H, s), 3.25 (1H, t,J=8.4 Hz), 3.14 (1H, td, J=14.8, 7.3 Hz), 2.67 (1H, t, J=8.3 Hz), 2.37(6H, s), 1.21 (3H, d, J=6.6 Hz).

ESI-MS found: 310 [M+H]⁺

Example 79 Synthesis of(3R*)-2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3-methyl-1H-indole-6-yl]aceticacid [79A] (hereinafter referred to as a compound [79A]) and(3S*)-2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3-methyl-1H-indole-6-yl]aceticacid [79B] (hereinafter referred to as a compound [79B])

The compound [78] obtained in Example 78 (26 mg) was optically resolvedby chiral column chromatography (CHIRALCEL (registered trademark) OD(CHRALCEL OD) manufactured by Daicel Corporation, 2 cm×25 cm; 0.1%trifluoroacetic acid, hexane/isopropyl alcohol=85/15; flow rate 20mL/min).(3R*)-2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3-methyl-1H-indole-6-yl]aceticacid [79A] (15 mg) as a pale brown solid was obtained from the precedingfraction (retention time: 5.3 minutes), and(3S*)-2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3-methyl-1H-indole-6-yl]aceticacid [79B] of the same (16 mg) as a pale brown solid was obtained fromthe posterior fraction (retention time: 10.8 minutes). (Both of themwere un-identified, and thus one of them was referred to as 3R*, and theother one as 3S* for convenience.)

Compound [79A]

1H-NMR and ESI-MS are the same as a compound [78].

Compound [79B]

1H-NMR and ESI-MS are the same as a compound [78].

Example 80 Synthesis of2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3,3-dimethyl-1H-indole-6-yl]aceticacid [80] (hereinafter referred to as a compound [80])

(1) Synthesis of 6-bromo-2,3-dihydro-3,2-dimethyl-0H-indole-2-one [80-1](hereinafter referred to as a compound [80-1])

Potassium tert-butoxide (6.2 g) was suspended in tetrahydrofuran (55mL), and a suspension of 6-bromo-1,3-dihydroindole-2-one (2.3 g) intetrahydrofuran (39 mL) and copper(I) bromide dimethyl sulfide complex(252 mg) were added. To the reaction mixture, methyl iodide (1.9 mL) wasadded at 0° C., and then the reaction mixture was stirred at 0° C. for 5minutes, and subsequently stirred at room temperature for 30 minutes. Tothe reaction mixture, an aqueous solution of ammonium chloride wasadded, and the reaction mixture was extracted with ethyl acetate. Theobtained organic layer was washed with brine, dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (1.4 g) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.65 (1H, brs), 7.18 (1H, dd, J=7.8, 2.0 Hz),7.06 (1H, d, J=2.0 Hz), 7.05 (1H, d, J=7.8 Hz), 1.38 (6H, s).

ESI-MS found: 240 [M+H]⁺

(2) Synthesis of tert-butyl6-bromo-2,3-dihydro-3,3-dimethyl-1H-indole-1-carboxylate [80-2](hereinafter referred to as a compound [80-2])

The titled compound (992 mg) as a colorless oil was prepared from thecompound [80-1] obtained in the process (1) (1.4 g) according to themethod of the process (2) of Example 78.

¹H-NMR (400 MHz, CDCl₃) δ: 8.05 (1H, s), 7.08 (1H, dd, J=1.7, 7.8 Hz),6.94 (1H, d, J=7.8 Hz), 3.70 (2H, s), 1.57 (9H, s), 1.30 (6H, s).

ESI-MS found: 270 [M-tBu+H]⁺

(3) Synthesis of methyl2-(2,3-dihydro-3,3-dimethyl-1H-indole-6-yl)acetate [80-3] (hereinafterreferred to as a compound [80-3])

The titled compound (20 mg) as a colorless oil was prepared from thecompound [80-2] obtained in the process (2) (992 mg) according to themethods of the processes (1) to (3) of Example 74.

¹H-NMR (400 MHz, CDCl₃) δ: 6.97 (1H, d, J=7.3 Hz), 6.63 (1H, d, J=7.6Hz), 6.57 (1H, s), 3.68 (3H, s), 3.53 (2H, s), 3.31 (2H, s), 1.29 (6H,s).

ESI-MS found: 220 [M+H]⁺

(4) Synthesis of methyl2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3,3-dimethyl-1H-indole-6-yl]acetate[80-4] (hereinafter referred to as a compound [80-4])

The titled compound (14 mg) as a colorless oil was prepared from thecompound [80-3] obtained in the process (3) (20 mg) and2,6-dimethylbenzyl chloride according to the method of the process (1)of Example 75.

¹H-NMR (400 MHz, CDCl₃) δ: 7.12 (1H, dd, J=8.2, 6.6 Hz), 7.08-7.02 (2H,m), 6.95 (1H, d, J=7.6 Hz), 6.60 (1H, d, J=7.3 Hz), 6.52 (1H, s), 4.22(2H, s), 3.71 (3H, s), 3.59 (2H, s), 2.84 (2H, s), 2.39 (6H, s), 1.19(6H, s).

ESI-MS found: 338 [M+H]⁺

(5) Synthesis of2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3,3-dimethyl-1H-indole-6-yl]aceticacid [80]

The titled compound (6 mg) as a white solid was prepared from thecompound [80-4] obtained in the process (4) (14 mg) according to themethod of the process (2) of Example 77.

¹H-NMR (400 MHz, CDCl₃) δ: 7.12 (1H, dd, J=8.2, 6.7 Hz), 7.07-7.02 (2H,m), 6.96 (1H, d, J=7.6 Hz), 6.62 (1H, d, J=7.3 Hz), 6.51 (1H, s), 4.22(2H, s), 3.62 (2H, s), 2.84 (2H, s), 2.37 (6H, s), 1.19 (6H, s).

ESI-MS found: 324 [M+H]⁺

Example 81 Synthesis of2,3-dihydro-1-(2,6-dimethylbenzyl)-1H-indole-6-carboxylic acid [81](hereinafter referred to as a compound [81])

(1) Synthesis of tert-butyl 2,3-dihydro-6-vinyl-1H-indole-1-carboxylate[81-1] (hereinafter referred to as a compound [81-1])

The titled compound (207 mg) as a white solid was prepared fromtert-butyl 6-bromo-2,3-dihydro-1H-indole-1-carboxylate obtained by themethod described in the document (WO 1998/43956 A) andtributyl(vinyl)tin according to the method of the process (2) of Example66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.96 (1H, brs), 7.09 (1H, d, J=7.6 Hz)7.01-6.92 (1H, brm), 6.69 (1H, dd, J=17.6-10.8 Hz), 5.80-5.66 (1H, brm),5.19 (1H, d, J=10.8 Hz), 4.06-3.91 (2H, brm), 3.07 (2H, t, J=8.7 Hz),1.57 (9H, s).

ESI-MS found: 190 [M-tBu+H]⁺

(2) Synthesis of methyl 2,3-dihydro-1H-indole-6-carboxylate [81-2](hereinafter referred to as a compound [81-2])

The titled compound (41 mg) as a pale brown solid was prepared from thecompound [81-1] obtained in the process (1) (207 mg) according to themethods of the processes (2) and (3) of Example 74.

¹H-NMR (400 MHz, CDCl₃) δ: 7.41 (1H, dd, J=7.6, 1.5 Hz), 7.26 (1H, d,J=1.5 Hz), 7.14 (1H, d, J=7.6 Hz), 3.87 (3H, s), 3.61 (2H, t, J=8.5 Hz),3.07 (2H, t, J=8.5 Hz).

ESI-MS found: 178 [M+H]⁺

(3) Synthesis of methyl2,3-dihydro-1-(2,6-dimethylbenzyl)-1H-indole-6-carboxylate [81-3](hereinafter referred to as a compound [81-3])

The titled compound (55 mg) as a white solid was prepared from thecompound [81-2] obtained in the process (2) (41 mg) and2,6-dimethylbenzyl chloride according to the method as described in theprocess (1) of Example 75.

¹H-NMR (400 MHz, CDCl₃) δ: 7.40 (1H, dd, J=7.6, 1.5 Hz), 7.23 (1H, d,J=1.5 Hz), 7.15-7.03 (4H, m), 4.27 (2H, s), 3.91 (3H, s), 3.15 (2H, t,J=8.3 Hz), 2.89 (2H, t, J=8.3 Hz), 2.39 (6H, s).

ESI-MS found: 296 [M+H]⁺

(4) Synthesis of2,3-dihydro-1-(2,6-dimethylbenzyl)-1H-indole-6-carboxylic acid [81]

To a solution of the compound [81-3] obtained in the process (3) (55 mg)in tetrahydrofuran (1.8 mL) was added 1N-sodium hydroxide (1.0 mL), andthen the reaction mixture was subjected to microwave irradiation at 120°C. for 20 minutes. Then, the reaction mixture was added 1N-hydrochloricacid, and extracted with ethyl acetate. The obtained organic layer waswashed with brine, dried over anhydrous sodium sulfate, filtered, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography to give thetitled compound (42 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.49 (1H, d, J=7.6 Hz), 7.28 (1H, s),7.17-7.10 (2H, m), 7.08-7.03 (2H, m), 4.28 (2H, s), 3.17 (2H, t, J=8.2Hz), 2.91 (2H, t, J=8.2 Hz), 2.40 (6H, s).

ESI-MS found: 282 [M+H]⁺

Example 82 Synthesis of2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indole-6-yl]acetic acid [82](hereinafter referred to as a compound [82])

To a solution of the compound obtained in the process (3) of Example 64[64-3] (272 mg) in N-methyl-2-pyrrolidone (4 mL) were added potassiumcarbonate (555 mg) and 2,6-dichlorobenzyl chloride (516 mg) at roomtemperature, and then the reaction mixture was subjected to microwaveirradiation at 130° C. for 40 minutes. The reaction mixture was quenchedwith water, and extracted with ethyl acetate. The obtained organic layerwas dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give a brown oil. The obtainedoil was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL).3N-sodium hydroxide (1 mL) was added at room temperature, and then thereaction mixture was subjected to microwave irradiation at 160° C. for10 minutes. The reaction mixture was quenched with water, and extractedwith ethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (194 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.48-7.32 (5H, m), 6.99 (1H, dd, J=8.1, 1.5Hz), 6.61 (1H, d, J=1.0 Hz), 5.50 (2H, s), 3.70 (2H, s), 2.20 (3H, s).

ESI-MS found: 348 [M+H]⁺

Example 83 Synthesis of potassium2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indole-6-yl]acetate [83](hereinafter referred to as a compound [83])

To a solution of the compound [82] (126 mg) in ethanol (2 mL) was addedan aqueous solution of 1N-potassium hydroxide (0.36 mL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (110 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.52-7.30 (5H, m), 7.05 (1H, d, J=8.1 Hz),6.51 (1H, s), 5.48 (2H, s), 3.61 (2H, s), 2.18 (3H, s).

ESI-MS found: 348 [M+K+2H]⁺

Example 84 Synthesis of2-[1-(2,3-dichlorobenzyl)-3-methyl-1H-indole-6-yl]acetic acid [84](hereinafter referred to as a compound [84])

The titled compound (33 mg) as a white solid was prepared from thecompound [64-3] obtained in the process (3) of Example 64 (55 mg) and2,3-dichlorobenzyl chloride (72 μL) according to the method of Example82.

¹H-NMR (400 MHz, CD₃OD) δ: 7.44 (1H, d, J=8.1 Hz), 7.40 (1H, d, J=7.8Hz), 7.17 (1H, s), 7.13-7.03 (2H, m), 6.93 (1H, s), 6.39 (1H, d, J=7.6Hz), 5.42 (2H, s), 3.52 (2H, s), 2.30 (3H, s).

ESI-MS found: 348 [M+H]⁺

Example 85 Synthesis of2-[1-(2,5-dimethylbenzyl)-3-methyl-1H-indole-6-yl]acetic acid [85](hereinafter referred to as a compound [85])

The titled compound (35 mg) as a white solid was prepared from thecompound [64-3] obtained in the process (3) of Example 64 (58 mg) and2,5-dimethylbenzyl chloride (81 μL) according to the method of Example82.

¹H-NMR (400 MHz, CD₃OD) δ: 7.41 (1H, d, J=8.1 Hz), 7.24 (1H, s),7.07-7.02 (2H, m), 6.95 (1H, d, J=7.1 Hz), 6.73 (1H, d, J=1.0 Hz), 6.54(1H, s), 5.21 (2H, s), 3.54 (2H, s), 2.27 (3H, s), 2.23 (3H, s), 2.14(3H, s).

ESI-MS found: 308 [M+H]⁺

Example 86 Synthesis of2-[1-(2-chloro-6-fluorobenzyl)-3-methyl-1H-indole-6-yl]acetic acid [86](hereinafter referred to as a compound [86])

The titled compound (38 mg) as a white solid was prepared from thecompound [64-3] obtained in the process (3) of Example 64 (50 mg) and2-chloro-6-fluorobenzyl chloride (72 μL) according to the method ofExample 82.

¹H-NMR (400 MHz, CD₃OD) δ: 7.46-7.26 (4H, m), 7.15 (1H, t, J=8.8 Hz),6.97 (1H, d, J=8.1 Hz), 6.85 (1H, s), 5.41 (2H, s), 3.68 (2H, s), 2.22(3H, s).

ESI-MS found: 332 [M+H]⁺

Example 87 Synthesis of2-[1-(2-chlorobenzyl)-3-methyl-1H-indole-6-yl]acetic acid [87](hereinafter referred to as a compound [87])

The titled compound (21 mg) as a white solid was prepared from thecompound [64-3] obtained in the process (3) of Example 64 (52 mg) and2-chlorobenzyl chloride (72 μL) according to the method of Example 82.

¹H-NMR (400 MHz, CD₃OD) δ: 7.48 (1H, d, J=8.1 Hz), 7.42 (1H, d, J=8.1Hz), 7.22 (1H, t, J=7.2 Hz), 7.14 (1H, s), 7.10 (1H, t, J=7.3 Hz),7.02-6.95 (2H, m), 6.60 (1H, d, J=7.6 Hz), 5.39 (2H, s), 3.63 (2H, s),2.30 (3H, s).

ESI-MS found: 314 [M+H]⁺

Example 88 Synthesis of2-{1-[(6-chlorobenzo[d][1,3]dioxol-5-yl)methyl]-3-methyl-1H-indole-6-yl}aceticacid [88] (hereinafter, referred to as a compound [88])

The titled compound (30 mg) as a white solid was prepared from thecompound [64-3] obtained in the process (3) of Example 64 (55 mg) and6-chloropiperonyl chloride (127 mg) according to the method of Example82.

¹H-NMR (400 MHz, CD₃OD) δ: 7.47 (1H, d, J=8.1 Hz), 7.17 (1H, s), 7.00(1H, d, J=8.1 Hz), 6.96 (1H, s), 6.92 (1H, s), 6.05 (1H, s), 5.89 (2H,s), 5.28 (2H, s), 3.65 (2H, s), 2.30 (3H, s).

ESI-MS found: 358 [M+H]⁺

Example 89 Synthesis of3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indole-6-yl]propionic acid [89](hereinafter referred to as a compound [89])

(1) Synthesis of 3-methyl-1-tosyl-1H-indole-6-carbaldehyde [89-1](hereinafter referred to as a compound [89-1])

To a solution of the compound [64-1] obtained in the process (1) ofExample 64 (1.01 g) in dichloromethane (30 mL), and Dess-Martinperiodinane (2.44 g) at 0° C., and then the reaction mixture was stirredat room temperature for 3 hours. To the reaction mixture, 10% aqueoussolution of sodium thiosulfate was added, and the reaction mixture wasextracted with chloroform. The obtained organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography to give the titled compound (1.00 g) as a brownsolid.

¹H-NMR (400 MHz, CDCl₃) δ: 10.09 (1H, s), 8.47 (1H, s), 7.81-7.76 (3H,m), 7.57 (1H, d, J=8.1 Hz), 7.52 (1H, s), 7.26-7.23 (2H, m), 2.35 (3H,s), 2.28 (3H, s).

(2) Synthesis of methyl(E)-3-(3-methyl-1-tosyl-1H-indole-6-yl)acrylate[89-2] (hereinafter referred to as a compound [89-2])

To a solution of the compound [89-1] obtained in the process (1) (1.0 g)in tetrahydrofuran (20 mL) was addedmethyl(triphenylphosphoranylidene)acetate (2.39 g) at room temperature,and then the reaction mixture was heated at reflux for 24 hours. Thereaction mixture was quenched with water, and extracted with ethylacetate. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (1.03 g) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.12 (1H, s), 7.81 (1H, d, J=16.1 Hz), 7.74(2H, d, J=8.3 Hz), 7.44 (2H, s), 7.37 (1H, s), 7.22 (2H, d, J=8.3 Hz),6.50 (1H, d, J=16.1 Hz), 3.83 (3H, s), 2.34 (3H, s), 2.24 (3H, s).

(3) Synthesis of methyl 3-(3-methyl-1-tosyl-1H-indole-6-yl)propionate[89-3] (hereinafter referred to as a compound [89-3])

The compound [89-2] (99 mg) obtained in the process (2) was suspended inmethanol (2 mL) and ethyl acetate (2 mL). To the mixture was added 5%palladium on carbon (38 mg) at room temperature, and then the reactionmixture was stirred at room temperature for 3 hours under hydrogenatmosphere. The palladium on carbon was filtered, and then the filtratewas concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography to give the titled compound(101 mg) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 7.82 (1H, s), 7.73 (2H, d, J=8.3 Hz), 7.35(1H, d, J=8.1 Hz), 7.26-7.18 (3H, m), 7.08 (1H, d, J=7.8 Hz), 3.68 (3H,s), 3.07 (2H, t, J=7.7 Hz), 2.67 (2H, t, J=7.8 Hz), 2.33 (3H, s), 2.21(3H, s).

(4) Synthesis of methyl 3-(3-methyl-1H-indole-6-yl)propionate [89-4](hereinafter referred to as a compound [89-4])

To a solution of the compound [89-3] obtained in the process (3) (94.5mg) in methanol (2 mL) was added an aqueous solution of 1N-sodiumhydroxide (1 mL), and then the reaction mixture was subjected tomicrowave irradiation at 160° C. for 10 minutes. The reaction mixturewas added 2N-hydrochloric acid, and extracted with ethyl acetate. Theobtained organic layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theobtained residue was dissolved in N,N-dimethylformamide (1 mL). To thesolution were added potassium carbonate (48 mg) and methyl iodide (18μL) at room temperature, and then the reaction mixture was stirred atroom temperature for 2 days. The reaction mixture was quenched withwater, and extracted with ethyl acetate. The obtained organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (41.6mg).

¹H-NMR (400 MHz, CDCl₃) δ: 7.88-7.73 (1H, br), 7.49 (1H, d, J=8.1 Hz),7.17 (1H, s), 6.97 (1H, d, J=7.3 z), 6.92 (1H, s), 3.67 (3H, s), 3.06(2H, t, J=7.8 Hz), 2.68 (2H, t, J=7.8 z), 2.31 (3H, s).

(5) Synthesis of3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indole-6-yl]propionic acid [89]

The titled compound (8.9 mg) as a pale brown solid was prepared from thecompound [89-4] obtained in the process (4) (41 mg) and2,6-dichlorobenzyl chloride (60 mg) according to the method of Example82.

¹H-NMR (400 MHz, CD₃OD) δ: 7.47 (2H, d, J=8.1 Hz), 7.41-7.33 (3H, m),6.93 (1H, d, J=8.1 Hz), 6.59 (1H, s), 5.47 (2H, s), 3.03 (2H, t, J=7.7Hz), 2.65 (2H, t, J=7.7 Hz), 2.19 (3H, s).

ESI-MS found: 362 [M+H]⁺

Example 90 Synthesis of3-acetyl-1-(2,6-dimethylbenzyl)-1H-indole-6-carboxylic acid [90](hereinafter referred to as a compound [90])

(1) Synthesis of methyl 3-acetyl-1H-indole-6-carboxylate [90-1](hereinafter referred to as a compound [90-1])

To a solution of methyl indole-6-carboxylate (1.01 g) in dichloromethane(30 mL) were added aluminum chloride (1.53 g) and acetyl chloride (0.5mL) at room temperature, and then the reaction mixture was stirred atroom temperature for 1 hour. To the reaction mixture was added asaturated aqueous solution of sodium hydrogen carbonate, and extractedwith ethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (625 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 8.34 (1H, s), 8.29 (1H, dd, J=8.5, 0.7 Hz),8.15 (1H, dd, J=1.5, 0.7 Hz), 7.87 (1H, dd, J=8.5, 1.5 Hz), 3.92 (3H,s), 2.54 (3H, s).

(2) Synthesis of methyl3-acetyl-1-(2,6-dimethylbenzyl)-1H-indole-6-carboxylate [90-2](hereinafter referred to as a compound [90-2])

To a solution of the compound [90-1] obtained in the process (1) (155mg) in N,N-dimethylformamide (2 mL) were added potassium carbonate (200mg) and 2,6-dimethylbenzyl chloride (170 mg) at room temperature. Thereaction mixture was subjected to microwave irradiation at 160° C. for20 minutes. The reaction mixture was quenched with water, and extractedwith ethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (135 mg) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.41 (1H, d, J=8.1 Hz), 8.32 (1H, s), 8.03(1H, dd, J=8.4, 1.3 Hz), 7.31-7.29 (1H, m), 7.26 (1H, s), 7.19 (2H, d,J=7.6 Hz), 5.34 (2H, s), 3.99 (3H, s), 2.39 (3H, s), 2.28 (6H, s).

(3) Synthesis of 3-acetyl-1-(2,6-dimethylbenzyl)-1H-indole-6-carboxylicacid [90]

To a solution of the compound [90-2] obtained in the process (2) (132mg) in methanol (3 mL) was added an aqueous solution of 1 N-sodiumhydroxide (3 mL) at room temperature, and then the reaction mixture wasstirred at 50° C. for 20 hours. The reaction mixture was added 1N-hydrochloric acid for acidification, and the precipitated solid wasfiltered to give the titled compound (160 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.46 (1H, d, J=8.3 Hz), 8.39 (1H, s), 8.10(1H, dd, J=8.5, 1.2 Hz), 7.32-7.30 (2H, m), 7.20 (2H, d, J=7.3 Hz), 5.37(2H, s), 2.40 (3H, s), 2.29 (6H, s).

Example 91 Synthesis of1-(2,6-dimethylbenzyl)-3-ethyl-1H-indole-6-carboxylic acid [91](hereinafter referred to as a compound [91])

(1) Synthesis of methyl 3-ethyl-1H-indole-6-carboxylate [91-1](hereinafter referred to as a compound [91-1])

To a solution of the compound [90-1] obtained in the process (1) ofExample 90 (455 mg) in tetrahydrofuran (15 mL), 1.2M tetrahydrofuransolution (6.0 mL) of a borane-tetrahydrofuran complex at roomtemperature, and then the reaction mixture was stirred at 50° C. for 1hour. To the reaction mixture was added a saturated aqueous solution ofammonium chloride, and the reaction mixture was extracted with ethylacetate. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (354 mg) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.12 (1H, d, J=0.7 Hz), 7.81 (1H, dd, J=8.3,1.5 Hz), 7.63 (1H, d, J=8.3 Hz), 7.15 (1H, t, J=1.2 Hz), 3.94 (3H, s),2.80 (2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.6 Hz).

(2) Synthesis of methyl1-(2,6-dimethylbenzyl)-3-ethyl-1H-indole-6-carboxylate [91-2](hereinafter referred to as a compound [91-2])

The titled compound (187 mg) as a yellow solid was prepared from thecompound [91-1] obtained in the process (1) (145 mg) and2,6-dimethylbenzyl chloride (171 mg) according to the method of theprocess (2) of Example 90.

¹H-NMR (400 MHz, CDCl₃) δ: 8.24 (1H, s), 7.82 (1H, dd, J=8.4, 1.3 Hz),7.62 (1H, d, J=8.3 Hz), 7.24-7.22 (1H, m), 7.14 (2H, d, J=7.6 Hz), 6.52(1H, s), 5.26 (2H, s), 3.97 (3H, s), 2.68 (2H, q, J=7.6 Hz), 2.26 (6H,s), 1.21 (3H, t, J=7.6 Hz).

(3) Synthesis of 1-(2,6-dimethylbenzyl)-3-ethyl-1H-indole-6-carboxylicacid [91]

The titled compound (160 mg) as a white solid was prepared from thecompound [91-2] obtained in the process (2) (184 mg) according to themethod of the process (3) of Example 90.

¹H-NMR (400 MHz, CDCl₃) δ: 8.32 (1H, s), 7.90 (1H, dd, J=8.4, 1.3 Hz),7.65 (1H, d, J=8.3 Hz), 7.28-7.22 (1H, m), 7.14 (2H, d, J=7.6 Hz), 6.56(1H, s), 5.29 (2H, s), 2.70 (2H, q, J=7.6 Hz), 2.28 (6H, s), 1.22 (3H,t, J=7.6 Hz).

ESI-MS found: 308 [M+H]⁺

Example 92 Synthesis of1-(2,6-dimethylbenzyl)-3-isopropyl-1H-indole-6-carboxylic acid [92](hereinafter referred to as a compound [92])

(1) Synthesis of methyl 3-isopropyl-1H-indole-6-carboxylate[92-1](hereinafter referred to as a compound [92-1])

To a solution of methyl indole-6-carboxylate (497 mg) in dichloromethane(15 mL) were added aluminum chloride (831 mg) and 2-bromopropane (0.27mL) at room temperature, and then the reaction mixture was stirred atroom temperature for 1 hour. To the reaction mixture was added asaturated aqueous solution of sodium hydrogen carbonate, and extractedwith ethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (65 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.34 (1H, s), 8.13 (1H, d, J=0.7 Hz),7.82-7.80 (1H, m), 7.68 (1H, d, J=8.3 Hz), 7.13 (1H, dd, J=2.4, 0.7 Hz),3.94 (3H, s), 3.28-3.18 (1H, m), 1.36 (6H, d, J=8.1 Hz).

(2) Synthesis of methyl1-(2,6-dimethylbenzyl)-3-isopropyl-1H-indole-6-carboxylate [92-2](hereinafter referred to as a compound [92-2])

The titled compound (68 mg) as a yellow solid was prepared from thecompound [92-1] obtained in the process (1) (65 mg) and2,6-dimethylbenzyl chloride (79 mg) according to the method of theprocess (2) of Example 90.

¹H-NMR (400 MHz, CDCl₃) δ: 8.24 (1H, s), 7.82 (1H, d, J=8.3 Hz), 7.67(1H, d, J=8.3 Hz), 7.25-7.23 (1H, m), 7.14 (2H, d, J=7.6 Hz), 6.50 (1H,s), 5.26 (2H, s), 3.97 (3H, s), 3.16-3.09 (1H, m), 2.27 (6H, s), 1.25(6H, d, J=6.8 Hz).

(3) Synthesis of1-(2,6-dimethylbenzyl)-3-isopropyl-1H-indole-6-carboxylic acid [92]

The titled compound (30 mg) as a white solid was prepared from thecompound [92-2] obtained in the process (2) (68 mg) according to themethod of the process (3) of Example 90.

¹H-NMR (400-MHz, CDCl₃) δ: 8.34 (1H, s), 7.92-7.90 (1H, m), 7.71 (1H, d,J=8.3 Hz), 7.27-7.23 (1H, m), 7.15 (2H, d, J=7.6 Hz), 6.56 (1H, s), 5.29(2H, d, J=3.4 Hz), 3.19-3.12 (1H, m), 2.29 (6H, s), 1.27 (6H, d, J=7.1Hz).

ESI-MS found: 322 [M+H]⁺

Example 93 Synthesis of2-{1-[(5-chlorothiophene-2-yl)methyl]-1H-indole-6-yl}acetic acid [93](hereinafter referred to as a compound [93])

The titled compound (15 mg) as a reddish brown solid was prepared fromthe compound [4-6] obtained in the process (6) of Example 4 (100 mg) and2-chloro-5-chloromethylthiophene (63 μL) according to the method of theprocess (7) of Example 4.

ESI-MS found: 306 [M+H]⁺

Example 94 Synthesis of3-chloro-1-(2,6-dimethylbenzyl)-6-(1H-tetrazole-5-yl)-1H-indole [94](hereinafter referred to as a compound [94])

(1) Synthesis of 3-chloro-1H-indole-6-carbonitrile [94-1] (hereinafterreferred to as a compound [94-1])

To a solution of 6-indole carbonitrile (1.0 g) in methanol (10 mL) wasadded N-chlorosuccinimide (1.2 g) at room temperature, and then thereaction mixture was stirred at room temperature for 16 hours. To thereaction mixture was added a saturated aqueous solution of sodiumhydrogen carbonate, and extracted with ethyl acetate. The obtainedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titledcompound (1.3 g) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.55-8.45 (1H, br), 7.75-7.70 (2H, m), 7.44(1H, dd, J=8.3, 1.2 Hz), 7.40 (1H, d, J=2.7 Hz).

(2) Synthesis of3-chloro-1-(2,6-dimethylbenzyl)-1H-indole-6-carbonitrile [94-2](hereinafter referred to as a compound [94-2])

To a solution of the compound [94-1] obtained in the process (1) (112mg) in N-methyl-2-pyrrolidone (3 mL) were added potassium carbonate (148mg) and 2,6-dimethylbenzyl chloride (122 mg) at room temperature, andthen the reaction mixture was subjected to microwave irradiation at 160°C. for 20 minutes. The reaction mixture was quenched with water, andextracted with ethyl acetate. The obtained organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography to give the titled compound (166 mg) as a yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.82 (1H, d, J=0.5 Hz), 7.69 (1H, d, J=8.3Hz), 7.44 (1H, dd, J=8.3, 1.2 Hz), 7.30-7.15 (1H, m), 7.15 (2H, d, J=7.6Hz), 6.75 (1H, s), 5.25 (2H, s), 2.26 (6H, s).

(3) Synthesis of3-chloro-1-(2,6-dimethylbenzyl)-6-(1H-tetrazole-5-yl)-1H-indole [94]

To a solution of the compound [94-2] obtained in the process (2) (164mg) in N,N-dimethylformamide (2 mL) were added ammonium chloride (47 mg)and sodium azide (45 mg) at room temperature, and then the reactionmixture was stirred at 100° C. for 17 hours. Furthermore, ammoniumchloride (55 mg) and sodium azide (45 mg) were added, and the reactionmixture was stirred at 100° C. for 24 hours. The reaction mixture wasquenched with water, and extracted with ethyl acetate. The obtainedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titledcompound (10 mg) as a brown solid.

¹H-NMR (400 MHz, CD₃OD) δ: 8.35 (1H, s), 7.82 (1H, dd, J=8.3, 1.5 Hz),7.71 (1H, d, J=8.3 Hz), 7.24 (1H, dd, J=8.4, 6.7 Hz), 7.16 (2H, d, J=7.8Hz), 6.71 (1H, s), 5.43 (2H, s), 2.28 (6H, s).

ESI-MS found: 338 [M+H]⁺

Example 95 Synthesis of1-(2,6-dimethylbenzyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid [95](hereinafter referred to as a compound [95])

(1) Synthesis of methyl1-(2,6-dimethylbenzyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylate [95-1](hereinafter referred to as a compound [95-1])

To a solution of methyl 1H-pyrrolo[3,2-b]pyridin-6-carboxylate (50 mg)in N-methyl-2-pyrrolidone (1 mL) were added potassium carbonate (158 mg)and 2,6-dimethylbenzyl chloride (91 mg), and then the reaction mixturewas subjected to microwave irradiation at 160° C. for 30 minutes. Thereaction mixture was quenched with water, and extracted with ethylacetate. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (21 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 9.14 (1H, s), 8.45 (1H, s), 7.25 (1H, t,J=7.3 Hz), 7.15 (2H, d, J=7.3 Hz), 7.02 (1H, d, J=3.0 Hz), 6.67 (1H, d,J=3.0 Hz), 5.33 (2H, s), 4.00 (3H, s), 2.26 (6H, s).

ESI-MS found: 295 [M+H]⁺

(2) Synthesis of1-(2,6-dimethylbenzyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid [95]

To a solution of the compound [95-1] obtained in the process (1) (21 mg)in tetrahydrofuran (1 mL) and methanol (1 mL) were added an aqueoussolution of 1N-sodium hydroxide (0.5 mL), and then the reaction mixturewas subjected to microwave irradiation at 140° C. for 30 minutes. Thereaction mixture was added with 1N-hydrochloric acid, and extracted withethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure to give the titled compound (13 mg) as a pale brownsolid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 13.01 (1H, brs), 8.91 (1H, d, J=1.7 Hz)8.53-8.51 (1H, m), 7.28 (1H, d, J=3.4 Hz), 7.23-7.17 (1H, m), 7.14-7.10(2H, m), 6.62 (1H, dd, J=3.4, 1.7 Hz), 5.48 (2H, s), 2.20 (6H, s).

ESI-MS found: 281 [M+H]⁺

Example 96 Synthesis of1-(2,6-dimethylbenzyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid [96](hereinafter referred to as a compound [96])

(1) Synthesis of 1H-pyrrolo[2,3-b]pyridine-7-oxide [96-1] (hereinafterreferred to as a compound [96-1])

To a solution of 1H-pyrrolo[2,3-b]pyridine (495 mg) in1,2-dimethoxyethane (20 mL) was added 3-chloroperbenzoic acid (1.48 g)at room temperature, and then the reaction mixture was stirred at roomtemperature for 2 hours. The reaction mixture was quenched with water,and extracted with chloroform. The obtained organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography to give the titled compound (360 mg) as a whitesolid.

¹H-NMR (400 MHz, CDCl₃) δ: 13.1 (1H, s), 8.23 (1H, d, J=6.1 Hz), 7.70(1H, d, J=7.8 Hz), 7.42 (1H, d, J=3.2 Hz), 7.06 (1H, dd, J=7.8, 6.3 Hz),6.56 (1H, d, J=3.2 Hz).

(2) Synthesis of 1H-pyrrolo[2,3-b]pyridine-6-carbonitrile [96-2](hereinafter referred to as a compound [96-2])

To a solution of the compound [96-1] obtained in the process (1) (360mg) in acetonitrile (5 mL) were added triethylamine (0.75 mL) andtrimethylsilyl cyanide (0.33 mL) at room temperature, and then thereaction mixture was stirred at 85° C. for 2 hours. To the reactionmixture was added aqueous solution of 1N-sodium hydroxide, and extractedwith chloroform. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (41 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.08 (1H, d, J=8.1 Hz), 7.71 (1H, dd, J=3.5,2.6 Hz), 7.52 (1H, d, J=8.1 Hz), 6.65 (1H, dd, J=3.7, 2.0 Hz).

(3) Synthesis of1-(2,6-dimethylbenzyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile [96-3](hereinafter referred to as a compound [96-3])

To a solution of the compound [96-2] obtained in the process (2) (40 mg)in N,N-dimethylformamide (2 mL) were added potassium carbonate (82 mg)and 2,6-dimethylbenzyl chloride (69 mg) at room temperature, and thenthe reaction mixture was stirred at room temperature for 3 hours. Thereaction mixture was quenched with water, and extracted with chloroform.The obtained organic layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive the titled compound (67 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.98 (1H, d, J=7.8 Hz), 7.49 (1H, d, J=8.1Hz), 7.22 (1H, dd, J=8.2, 7.0 Hz), 7.12 (2H, d, J=7.6 Hz), 6.96 (1H, d,J=3.4 Hz), 6.46 (1H, d, J=3.7 Hz), 5.49 (2H, s), 2.27 (6H, s).

(4) Synthesis of1-(2,6-dimethylbenzyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid [96]

To a solution of the compound [96-3] obtained in the process (3) (66 mg)in ethanol (2 mL) was added an aqueous solution of 3N-sodium hydroxide(2 mL) at room temperature, and then the reaction mixture was heated atreflux for 1 hour. To the reaction mixture was added 1N-hydrochloricacid, and the precipitated solid was filtered to give the titledcompound (15 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 8.08 (1H, d, J=8.1 Hz), 7.96 (1H, d, J=8.1Hz), 7.20-7.18 (1H, m), 7.11 (2H, d, J=7.6 Hz), 6.97 (1H, d, J=3.7 Hz),6.51 (1H, d, J=3.7 Hz), 5.62 (2H, s), 2.25 (6H, s).

Example 97 Synthesis of2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]acetic acid [97](hereinafter referred to as a compound [97])

(1) Synthesis of 6-bromo-1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole[97-1] (hereinafter referred to as a compound [97-1])

The titled compound (10.4 g) as a white solid was prepared from the6-bromo-3-methyl-1H-indazole (9.57 g) obtained with the method describedin the document (JP 2009-528363 W) and 2,6-dichlorobenzyl chloride (9.79g) according to the method of the process (1) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.55 (1H, s), 7.47 (1H, d, J=8.5 Hz), 7.38(2H, d, J=8.1 Hz), 7.25 (1H, d, J=5.9 Hz), 7.22-7.20 (1H, m), 5.66 (2H,s), 2.50 (3H, s).

(2) Synthesis of 6-allyl-1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole[97-2] (hereinafter referred to as a compound [97-2])

The titled compound (3.25 g) as a white solid was prepared from thecompound [97-1] obtained in the process (1) (5.02 g) and allyltributyltin (4.6 mL) according to the method of the process (2) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.53-7.52 (1H, m), 7.37-7.36 (2H, m),7.25-7.18 (2H, m), 6.95 (1H, d, J=8.1 Hz), 6.03-5.94 (1H, m), 5.69 (2H,s), 5.12-5.10 (2H, m), 3.51-3.49 (2H, m), 2.51 (3H, s).

(3) Synthesis of2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]acetaldehyde [97-3](hereinafter referred to as a compound [97-3])

The titled compound (1.03 g) as a white solid was prepared from thecompound [97-2] obtained in the process (2) (3.25 g) according to themethod of the process (3) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 9.77 (1H, t, J=2.3 Hz), 7.62 (1H, d, J=8.3Hz), 7.37 (2H, d, J=8.1 Hz), 7.25-7.23 (2H, m), 6.95 (1H, d, J=8.3 Hz),5.70 (2H, s), 3.80 (2H, d, J=2.2 Hz), 2.52 (3H, s).

(4) Synthesis of2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]acetic acid [97]

The titled compound (1.06 g) as a white solid was prepared from thecompound [97-3] obtained in the process (3) (1.03 g) according to themethod of the process (4) of Example 66.

¹H-NMR (400 MHz, CD₃OD) δ: 7.62 (1H, d, J=8.3 Hz), 7.46-7.44 (3H, m),7.35-7.33 (1H, m), 7.09 (1H, d, J=8.3 Hz), 5.72 (2H, s), 3.73 (2H, s),2.46 (3H, s).

ESI-MS found: 349 [M+H]⁺

Example 98 Synthesis of potassium2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]acetate [98](hereinafter referred to as a compound [98])

To a solution of the compound [97] (118 mg) in ethanol (5 mL) was addedan aqueous solution of 1N-potassium hydroxide (0.34 mL) at roomtemperature, and then the reaction mixture was stirred at roomtemperature for 10 minutes. The reaction mixture was concentrated underreduced pressure to give the titled compound (128 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.56 (1H, d, J=8.3 Hz), 7.47-7.43 (3H, m),7.35-7.31 (1H, m), 7.15 (1H, d, J=8.1 Hz), 5.70 (2H, s), 3.61 (2H, s),2.44 (3H, s).

ESI-MS found: 349 [M+K+2H]⁺

Example 99 Synthesis of2-[1-(2,3-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]acetic acid [99](hereinafter referred to as a compound [99])

(1) Synthesis of 6-bromo-1-(2,3-dichlorobenzyl)-3-methyl-1H-indazole[99-1] (hereinafter referred to as a compound [99-1])

The titled compound (228 mg) as a white solid was prepared from the6-bromo-3-methyl-1H-indazole (152 mg) obtained with the method describedin the document (JP 2009-528363 W) and 2,3-dichlorobenzyl chloride (215mg) according to the method of the process (1) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.84-7.82 (2H, m), 7.70 (1H, d, J=8.4 Hz),7.40 (1H, d, J=8.1 Hz), 7.08-7.04 (1H, m), 6.57-6.54 (1H, m), 5.73 (2H,s), 2.65 (3H, s).

(2) Synthesis of2-[1-(2,3-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]acetic acid [99]

The titled compound (50 mg) as a white solid was prepared from thecompound [99-1] obtained in the process (1) according to the method ofthe processes (2) to (4) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.65 (1H, d, J=8.3 Hz), 7.34 (1H, d, J=7.3Hz), 7.17 (1H, s), 7.09 (1H, d, J=8.3 Hz), 7.02-7.00 (1H, m), 6.50 (1H,d, J=7.8 Hz), 5.62 (2H, s), 3.74 (2H, s), 2.59 (3H, s).

ESI-MS found: 349 [M+H]⁺

Example 100 Synthesis of potassium2-[1-(2,3-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]acetate [100](hereinafter referred to as a compound [100])

To a solution of the compound [99] (37 mg) in ethanol (2 mL) was addedan aqueous solution of 1N-potassium hydroxide (106 μL) at roomtemperature, and then the reaction mixture was stirred at roomtemperature for 10 minutes. The reaction mixture was concentrated underreduced pressure to give the titled compound (38 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.63 (1H, d, J=8.3 Hz), 7.43 (1H, d, J=7.6Hz), 7.34 (1H, s), 7.18 (1H, d, J=8.3 Hz), 7.11-7.10 (1H, m), 6.45 (1H,d, J=7.8 Hz), 5.66 (2H, s), 3.57 (2H, s), 2.54 (3H, s).

ESI-MS found: 349 [M+K+2H]⁺

Example 101 Synthesis of2-[1-(2,5-dimethylbenzyl)-3-methyl-1H-indazole-6-yl]acetic acid [101](hereinafter referred to as a compound [101])

(1) Synthesis of 6-bromo-1-(2,5-dimethylbenzyl)-3-methyl-1H-indazole[101-1] (hereinafter referred to as a compound [101-1])

The titled compound (158 mg) as a white solid was prepared from6-bromo-3-methyl-1H-indazole (148 mg) obtained with the method describedin the document (JP 2009-528363 W) and 2,5-dimethylbenzyl chloride (164mg) according to the method of the process (1) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.59 (1H, d, J=4.1 Hz), 7.06-7.04 (2H, m),6.98-6.96 (2H, m), 6.61 (1H, s), 5.44 (2H, s), 2.58 (3H, s), 2.31 (3H,s), 2.19 (3H, s).

(2) Synthesis of2-[1-(2,5-dimethylbenzyl)-3-methyl-1H-indazole-6-yl]acetic acid [101]

The titled compound (59 mg) as a white solid was prepared from thecompound [101-1] obtained in the process (1) according to the methods ofthe processes (2) to (4) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.64 (1H, d, J=8.3 Hz), 7.13 (1H, s),7.06-7.04 (2H, m), 6.98-6.96 (1H, m), 6.60 (1H, s), 5.46 (2H, s), 3.72(2H, s), 2.59 (3H, s), 2.29 (3H, s), 2.17 (3H, s).

ESI-MS found: 309 [M+H]⁺

Example 102 Synthesis of2-[1-(2-chloro-6-methylbenzyl)-3-methyl-1H-indazole-6-yl]acetic acid[102] (hereinafter referred to as a compound [102])

(1) Synthesis of6-bromo-3-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indazole [102-1](hereinafter referred to as a compound [102-1])

To a solution of 6-bromo-3-methyl-1H-indazole (4.4 g) obtained with themethod described in the document (JP-A No. 2009-528363) in chloroform(50 mL) were added diisopropylethylamine (5.3 mL) and2-(trimethylsilyl)ethoxymethyl chloride (4.4 mL) at room temperature,and then the reaction mixture was stirred at room temperature for 22hours. To the reaction mixture was added 5% aqueous solution ofpotassium hydrogen sulfate, and the reaction mixture was extracted withethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (1.8 g) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.69 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.27(1H, d, J=6.8 Hz), 5.61 (2H, s), 3.54 (2H, t, J=8.2 Hz), 2.55 (3H, s),0.89 (2H, t, J=8.2 Hz), 0.00 (9H, s).

(2) Synthesis of tert-butyl2-[3-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indazole-6-yl]acetate[102-2] (hereinafter referred to as a compound [102-2])

To a solution of dicyclohexylamine (1.8 mL) in toluene (26 mL) was added1.63M hexane solution of n-butyl lithium (5.5 mL) at 0° C., and then thereaction mixture was stirred at 0° C. for 30 minutes. To the reactionmixture was added tert-butyl acetate (1.1 mL) at 0° C., and then thereaction mixture was stirred at 0° C. for 30 minutes. The obtainedsolution was added to the mixture of the compound [102-1] obtained inthe process (1) (1.8 g), bis(dibenzylideneacetone)palladium(0) (303 mg)and 2-(dicyclohexylphosphino)-2′-(dimethylamino)biphenyl (207 mg) atroom temperature, and the reaction mixture was stirred for 48 hours. Thereaction mixture was quenched with water, and extracted with ethylacetate. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (422 mg) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 7.59 (1H, d, J=8.1 Hz), 7.40 (1H, s), 7.10(1H, d, J=8.1 Hz), 5.64 (2H, s), 3.66 (2H, s), 3.55 (2H, t, J=8.2 Hz),2.55 (3H, s), 1.44 (9H, s), 0.89 (2H, t, J=8.3 Hz), 0.00 (9H, s).

(3) Synthesis of 2-(3-methyl-1H-indazole-6-yl)acetic acid [102-3](hereinafter referred to as a compound [102-3])

To the compound [102-2] obtained in the process (2) (193 mg) were addedwater (0.5 mL) and trifluoroacetic acid (4.7 mL) at room temperature,and then the reaction mixture was stirred at room temperature for 1.5hours. The reaction mixture was quenched with water, and extracted withethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (61 mg) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 7.76 (1H, s), 7.68 (1H, d, J=8.5 Hz), 7.18(1H, d, J=8.3 Hz), 3.82 (2H, s), 2.66 (3H, s).

(4) Synthesis of methyl 2-(3-methyl-1H-indazole-6-yl)acetate [102-4](hereinafter referred to as a compound [102-4])

To a solution of the compound [102-3] obtained in the process (3) (340.5mg) in tetrahydrofuran (3.6 mL) were added methanol (3.6 mL) and 0.6Mhexane solution of trimethylsilyldiazomethane (3.6 mL) at roomtemperature, and then the reaction mixture was stirred at roomtemperature for 24 hours. The reaction solution was concentrated underreduced pressure, and then The obtained residue was purified by silicagel column chromatography to give the titled compound (236 mg) as awhite solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.63 (1H, d, J=8.3 Hz), 7.34 (1H, s), 7.07(1H, d, J=8.3 Hz), 3.76 (2H, s), 3.70 (3H, s), 2.57 (3H, s).

(5) Synthesis of2-[1-(2-chloro-6-methylbenzyl)-3-methyl-1H-indazole-6-yl]acetic acid[102]

To a solution of the compound [102-4] obtained in the process (4) (19.4mg) in N,N-dimethylformamide (0.5 mL) were added potassium carbonate(20.7 mg) and 2-chloro-6-methylbenzyl chloride (25.0 mg) at roomtemperature, and then the reaction mixture was stirred at roomtemperature for 20 hours. The reaction mixture was quenched with water,and extracted with ethyl acetate. The obtained organic layer was driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give a colorless oil. To theobtained colorless oil was added methanol (0.2 mL) and tetrahydrofuran(0.2 mL). To the solution was added an aqueous solution of 1N-sodiumhydroxide (0.2 mL) at room temperature, and then the reaction mixturewas stirred at room temperature for 40 minutes. The reaction mixture wasadded 1N-hydrochloric acid for acidification, and extracted withchloroform. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by reverse phase preparativeliquid chromatography to give the titled compound (6.0 mg) as a whitesolid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.60 (1H, d, J=8.3 Hz), 7.35 (1H, s), 7.30(1H, d, J=7.6 Hz), 7.21 (1H, t, J=7.7 Hz), 7.15 (1H, d, J=7.3 Hz), 7.05(1H, d, J=8.3 Hz), 5.61 (2H, s), 3.70 (2H, s), 2.46 (3H, s), 2.29 (3H,s).

ESI-MS found: 329 [M+H]⁺

Example 103 Synthesis of potassium2-[1-(2-chloro-6-methylbenzyl)-3-methyl-1H-indazole-6-yl]acetate [103](hereinafter referred to as a compound [103])

To a solution of the compound [102] (33.1 mg) in ethanol (3.0 mL) wasadded an aqueous solution of 1N-potassium hydroxide (0.1 mL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (35.5 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.56 (1H, d, J=8.3 Hz), 7.39 (1H, s), 7.29(1H, d, J=7.8 Hz), 7.20 (1H, t, J=7.8 Hz), 7.15-7.13 (2H, m), 5.60 (2H,s), 3.60 (2H, s), 2.45 (3H, s), 2.28 (3H, s).

ESI-MS found: 329 [M+K+2H]⁺

Example 104 Synthesis of2-[1-(2-chloro-6-fluorobenzyl)-3-methyl-1H-indazole-6-yl]acetic acid[104] (hereinafter referred to as a compound [104])

To a solution of the compound [102-4] obtained in the process (4) ofExample 102 (60.9 mg) in N,N-dimethylformamide (1.6 mL) were addedpotassium carbonate (221.2 mg) and 2-chloro-6-fluorobenzyl chloride(0.16 mL) at room temperature, and then the reaction mixture was stirredat 80° C. for 18 hours. The reaction mixture was quenched with water,and extracted with diethyl ether. The obtained organic layer was driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography. To a solution of the purifiedcompound in methanol (1 mL) were added 1N-sodium hydroxide (1 mL) andtetrahydrofuran (1 mL), and then the reaction mixture was stirred at 65°C. for 16 hours. The reaction mixture was added 1 N-hydrochloric acidfor acidification, and extracted with chloroform. The obtained organiclayer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by reverse phase preparative liquid chromatography to givethe titled compound 4.5 mg as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.59 (1H, d, J=8.3 Hz), 7.39 (1H, s),7.23-7.19 (2H, m), 7.07-6.98 (2H, m), 5.64 (2H, s), 3.79 (2H, s), 2.53(3H, s).

ESI-MS found: 333 [M+H]⁺

Example 105 Synthesis of2-[1-(3,5-dimethylisoxazole-4-ylmethyl)-3-methyl-1H-indazole-6-yl]aceticacid [105] (hereinafter referred to as a compound [105])

The titled compound (16.5 mg) as a white solid was prepared from thecompound [102-4] obtained in the process (4) of Example 102 (21.0 mg)and 4-(chloromethyl)-3,5-dimethylisoxazole according to the method ofthe process (5) of Example 102.

¹H-NMR (400 MHz, CDCl₃) δ: 7.59 (1H, d, J=8.3 Hz), 7.19 (1H, s), 7.05(1H, d, J=8.1 Hz), 5.21 (2H, s), 3.75 (2H, s), 2.52 (3H, s), 2.34 (3H,s), 2.12 (3H, s).

ESI-MS found: 300 [M+H]⁺

Example 106 Synthesis of2-{1-[(5-chlorobenzo[b]thiophene-3-yl)methyl]-3-methyl-1H-indazole-6-yl}aceticacid [106] (hereinafter referred to as a compound [106])

The titled compound (4.3 mg) as a brown solid was prepared from thecompound [102-4] obtained in the process (4) of Example 102 (24.7 mg)and 3-bromomethyl-5-chlorobenzo[b]thiophene according to the method ofthe process (5) of Example 102.

¹H-NMR (400 MHz, CDCl₃) δ: 7.84 (1H, s), 7.72 (1H, d, J=8.5 Hz), 7.63(1H, d, J=8.3 Hz), 7.31-7.23 (2H, m), 7.13 (1H, s), 7.06 (1H, d, J=8.3Hz), 5.68 (2H, s), 3.74 (2H, s), 2.59 (3H, s).

ESI-MS found: 371 [M+H]⁺

Example 107 Synthesis of2-[3-methyl-1-(naphthalene-1-ylmethyl)-1H-indazole-6-yl]acetic acid[107] (hereinafter referred to as a compound [107])

The titled compound (19.5 mg) as a white solid was prepared from thecompound [102-4] obtained in the process (4) of Example 102 (26.3 mg)and 1-(chloromethyl)naphthalene according to the method of the process(5) of Example 102.

¹H-NMR (400 MHz, CDCl₃) δ: 8.13 (1H, d, J=8.1 Hz), 7.88 (1H, d, J=7.3Hz), 7.78 (1H, d, J=8.1 Hz), 7.66 (1H, d, J=8.3 Hz), 7.55 (1H, t, J=8.4Hz), 7.51 (1H, t, J=8.4 Hz), 7.33 (1H, t, J=7.7 Hz), 7.16 (1H, s), 7.07(1H, d, J=7.8 Hz), 6.92 (1H, d, J=6.8 Hz), 6.02 (2H, s), 3.70 (2H, s),2.62 (3H, s).

ESI-MS found: 331 [M+H]⁺

Example 108 Synthesis of2-[3-methyl-1-(2,4,6-trimethylbenzyl)-1H-indazole-6-yl]acetic acid [108](hereinafter referred to as a compound [108])

The titled compound (10.3 mg) as a white solid was prepared from thecompound [102-4] obtained in the process (4) of Example 102 (21.2 mg)and 2,4,6-trimethylbenzyl chloride according to the method of theprocess (5) of Example 102.

¹H-NMR (400 MHz, CDCl₃) δ: 7.56 (1H, d, J=8.3 Hz), 6.99 (1H, d, J=8.3Hz), 6.91 (1H, s), 6.88 (2H, s), 5.43 (2H, s), 3.67 (2H, s), 2.51 (3H,s), 2.27 (9H, s).

ESI-MS found: 323 [M+H]⁺

Example 109 Synthesis of2-[1-(2-chloro-6-cyanobenzyl)-3-methyl-1H-indazole-6-yl]acetic acid[109] (hereinafter referred to as a compound [109])

To a solution of the compound [97] (30.1 mg) in N,N-dimethylformamide(0.9 mL) were added zinc cyanide (20.2 mg),tris(dibenzylideneacetone)dipalladium(0) (7.9 mg) and2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (5.1 mg) at roomtemperature, and then the reaction mixture was subjected to microwaveirradiation at 150° C. for 2 hours. The reaction mixture was extractedwith ethyl acetate, and then the obtained organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by reversephase preparative liquid chromatography to give the titled compound (5.0mg) as a yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.78 (1H, d, J=7.6 Hz), 7.74 (1H, d, J=8.1Hz), 7.63 (1H, d, J=8.1 Hz), 7.54-7.52 (2H, m), 7.11 (1H, d, J=8.3 Hz),5.73 (2H, s), 3.77 (2H, s), 2.46 (3H, s).

ESI-MS found: 340 [M+H]⁺

Example 110 Synthesis of potassium2-[1-(2-chloro-6-cyanobenzyl)-3-methyl-1H-indazole-6-yl]acetate [110](hereinafter referred to as a compound [110])

To a solution of compound [109] (11.2 mg) in ethanol (1.1 mL) was addedan aqueous solution of 1 N-potassium hydroxide (33 μL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (12.5 mg) as a yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.78 (1H, d, J=7.8 Hz), 7.74 (1H, d, J=8.1Hz), 7.57 (1H, d, J=8.3 Hz), 7.54-7.50 (2H, m), 7.17 (1H, d, J=8.3 Hz),5.72 (2H, s), 3.63 (2H, s), 2.45 (3H, s).

ESI-MS found: 340 [M+K+2H]⁺

Example 111 Synthesis of2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]propionic acid [111](hereinafter referred to as a compound [111])

(1) Synthesis of tert-butyl[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]acetate [111-1](hereinafter referred to as a compound [111-1])

To a solution of dicyclohexylamine (0.4 mL) in toluene (5.7 mL) wasadded 1.63M hexane solution of n-butyl lithium (1.2 mL) at 0° C., andthe reaction mixture was stirred at 0° C. for 30 minutes. Subsequently,tert-butyl acetate was added at 0° C., and the reaction mixture wasstirred at 0° C. for 30 minutes. The obtained solution was added to themixture of the compound [97-1] obtained in the process (1) of Example 97(421 mg), bis(dibenzylideneacetone)palladium(0) (196 mg) andtri-tert-butylphosphonium tetrafluoroborate (99 mg), and the reactionmixture was stirred at room temperature for 18 hours. The reactionmixture was quenched with water, and extracted with ethyl acetate. Theobtained organic layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive the titled compound (422 mg) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 7.55 (1H, d, J=8.3 Hz), 7.36 (2H, d, J=8.1Hz), 7.29 (1H, s), 7.22 (1H, t, J=8.1 Hz), 7.03 (1H, d, J=8.3 Hz), 5.69(2H, s), 3.63 (2H, s), 2.50 (3H, s), 1.43 (9H, s).

(2) Synthesis of2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]propionic acid [111]

The compound [111-1] obtained in the process (1) (45.3 mg) and methyliodide (9.1 μL) were dissolved in tetrahydrofuran (0.6 mL). To thesolution was added 0.5M toluene solution of potassiumbis(trimethylsilyl)amide (0.3 mL) at 0° C., and then the reactionmixture was stirred at room temperature for 9 hours. The reactionmixture was quenched with a saturated aqueous solution of ammoniumchloride, and extracted with ethyl acetate. The obtained organic layerwas dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography. To the purified compound was addedwater (50 μL) and trifluoroacetic acid (500 μL) at room temperature, andthen the reaction mixture was stirred at room temperature for 1.5 hours.The reaction mixture was quenched with water, and extracted with ethylacetate. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by reverse phase preparativeliquid chromatography to give the titled compound (13.7 mg) as a whitesolid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.61 (1H, d, J=8.3 Hz), 7.44 (2H, d, J=4.9Hz), 7.42 (1H, s), 7.33 (1H, t, J=8.1 Hz), 7.11 (1H, d, J=8.3 Hz), 5.72(2H, s), 3.84 (1H, q, J=7.1 Hz), 2.46 (3H, s), 1.50 (3H, d, J=7.1 Hz).

ESI-MS found: 364 [M+H]⁺

Example 112 Synthesis of2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]-2-methylpropionicacid [112] (hereinafter referred to as a compound [112])

The titled compound (3.8 mg) as a white solid was prepared from thecompound [111-1] obtained in the process (1) of Example 111 (30.0 mg)and methyl iodide (13.8 μL) according to the method of the process (2)of Example 111.

¹H-NMR (400 MHz, CDCl₃) δ: 7.58 (1H, d, J=8.5 Hz), 7.34 (2H, d, J=8.1Hz), 7.31 (1H, s), 7.20 (1H, t, J=8.0 Hz), 7.15 (1H, d, J=8.4 Hz), 5.77(2H, s), 2.53 (3H, s), 1.61 (6H, s).

ESI-MS found: 378 [M+H]⁺

Example 113 Synthesis of2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]butyric acid [113](hereinafter referred to as a compound [113])

The titled compound (21.6 mg) as a white solid was prepared from thecompound [111-1] obtained in the process (1) of Example 111 (54.5 mg)and ethyl iodide (32 μL) according to the method of the process (2) ofExample 111.

¹H-NMR (400 MHz, CDCl₃) δ: 7.62 (1H, d, J=8.3 Hz), 7.32 (2H, d, J=8.1Hz), 7.26 (1H, s), 7.18 (1H, t, J=8.1 Hz), 7.12 (1H, d, J=8.3 Hz), 5.80(2H, s), 3.56 (1H, t, J=7.6 Hz), 2.56 (3H, s), 2.16-2.05 (1H, m),1.87-1.76 (1H, m), 0.89 (3H, t, J=7.3 Hz).

ESI-MS found: 378 [M+H]⁺

Example 114 Synthesis of 2-(3-methyl-1-phenethyl-1H-indazole-6-yl)aceticacid [114] (hereinafter referred to as a compound [114])

The titled compound (1.9 mg) as a white solid was prepared from thecompound [102-4] obtained in the process (4) of Example 102 (42.6 mg)and (2-chloroethyl)benzene according to the method of the process (5) ofExample 102.

¹H-NMR (400 MHz, CDCl₃) δ: 7.59 (1H, d, J=8.3 Hz), 7.26-7.18 (3H, m),7.12 (2H, d, J=6.8 Hz), 7.03-7.00 (2H, m), 4.51 (2H, t, J=7.4 Hz), 3.72(2H, s), 3.15 (2H, t, J=7.4 Hz), 2.58 (3H, s).

ESI-MS found: 295 [M+H]⁺

Example 115 Synthesis of2-[3-methyl-1-(quinoline-8-ylmethyl)-1H-indazole-6-yl]acetic acid [115](hereinafter referred to as a compound [115])

The titled compound (73.8 mg) as a yellow solid was prepared from thecompound [102-4] obtained in the process (4) of Example 102 (102 mg) and8-(bromomethyl)quinoline according to the method of the process (5) ofExample 102.

¹H-NMR (400 MHz, CD₃OD) δ: 8.98 (1H, d, J=2.7 Hz), 8.32 (1H, d, J=6.8Hz), 7.82 (1H, d, J=8.1 Hz), 7.68 (1H, d, J=8.3 Hz), 7.56 (1H, dd, J=8.3Hz, 4.1 Hz), 7.45 (1H, s), 7.40 (1H, t, J=7.7 Hz), 7.10 (1H, t, J=8.3Hz), 6.98 (1H, d, J=6.8 Hz), 6.23 (2H, s), 3.67 (2H, s), 2.57 (3H, s).

ESI-MS found: 332 [M+H]⁺

Example 116 Synthesis of potassium2-[3-methyl-1-(quinoline-8-ylmethyl)-1H-indazole-6-yl]acetate [116](hereinafter referred to as a compound [116])

To a solution of the compound [115] (73.8 mg) in ethanol (7.4 mL), wasadded an aqueous solution of 1N-potassium hydroxide (223 μL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (82.3 mg) as a yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 8.99 (1H, d, J=2.8), 8.32 (1H, d, J=7.2 Hz),7.81 (1H, d, J=8.3 Hz), 7.64 (1H, d, J=8.3 Hz), 7.56 (1H, dd, J=8.3 Hz,4.4 Hz), 7.41 (1H, s), 7.37 (1H, t, J=7.7 Hz), 7.17 (1H, d, J=8.3 Hz),6.85 (1H, d, J=7.1 Hz), 6.23 (2H, s), 3.54 (2H, s), 2.57 (3H, s).

ESI-MS found: 332 [M+K+2H]⁺

Example 117 Synthesis of1-(2,6-dimethylbenzyl)-3-methyl-1H-indazole-6-carboxylic acid [117](hereinafter referred to as a compound [117])

(1) Synthesis of ethyl1-(2,6-dimethylbenzyl)-3-methyl-1H-indazole-6-carboxylate [117-1](hereinafter referred to as a compound [117-1])

To a solution of the compound [66-1] obtained in the process (1) ofExample 66 (1.74 g) in ethanol (20 mL) were added triethylamine (2.2 mL)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52 mg)at room temperature, and then the reaction mixture was flushed withcarbon monoxide and heated at reflux for 18 hours. The reaction mixturewas quenched with water, and extracted with ethyl acetate. The obtainedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titledcompound (639 mg) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.77 (1H, s), 7.73 (1H, d, J=8.3 Hz), 7.63(1H, d, J=8.3 Hz), 7.20-7.18 (1H, m), 7.10 (2H, d, J=7.6 Hz), 5.55 (2H,s), 4.36 (2H, q, J=7.1 Hz), 2.55 (3H, s), 2.35 (6H, s), 1.40 (3H, t,J=7.2 Hz).

(2) Synthesis of1-(2,6-dimethylbenzyl)-3-methyl-1H-indazole-6-carboxylic acid [117]

To a solution of the compound [117-1] obtained in the process (1) (636mg) in ethanol (10 mL) was added an aqueous solution of 1N-sodiumhydroxide (10 mL) at room temperature, and then the reaction mixture wasstirred at 70° C. for 2 hours. To the reaction mixture was added1N-hydrochloric acid, and the precipitated solid was filtered to givethe titled compound (568 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 8.04 (1H, s), 7.73 (2H, s), 7.15-7.13 (1H,m), 7.07 (2H, d, J=7.6 Hz), 5.59 (2H, s), 2.52 (3H, s), 2.29 (6H, s).

ESI-MS found: 295 [M+H]⁺

Example 118 Synthesis of potassium1-(2,6-dimethylbenzyl)-3-methyl-1H-indazole-6-carboxylate [118](hereinafter referred to as a compound [118])

To a solution of the compound [117] (568 mg) in ethanol (20 mL) wasadded an aqueous solution of 1N-potassium hydroxide (1.93 mL) at roomtemperature, and then the reaction mixture was stirred at roomtemperature for 10 minutes. The reaction mixture was concentrated underreduced pressure to give the titled compound (636 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 8.06 (1H, s), 7.73 (1H, d, J=8.3 Hz), 7.62(1H, d, J=8.5 Hz), 7.12-7.11 (1H, m), 7.05 (2H, d, J=7.3 Hz), 5.53 (2H,s), 2.48 (3H, s), 2.29 (6H, s).

ESI-MS found: 295 [M+K−2H]⁺

Example 119 Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-carboxylic acid [119](hereinafter referred to as a compound [119])

The titled compound (28 mg) as a white solid was prepared from thecompound [97-1] obtained in the process (1) of Example 97 (60 mg)according to the method described in Example 117.

¹H-NMR (400 MHz, CD₃OD) δ: 8.28 (1H, s), 7.78-7.75 (2H, m), 7.45 (2H, d,J=7.8 Hz), 7.36-7.34 (1H, m), 5.81 (2H, s), 2.50 (3H, s).

ESI-MS found: 335 [M+H]⁺

Example 120 Synthesis of1-(2,3-dichlorobenzyl)-3-methyl-1H-indazole-6-carboxylic acid [120](hereinafter referred to as a compound [120])

The titled compound (40 mg) as a white solid was prepared from thecompound [99-1] obtained in the process (1) of Example 99 (87 mg)according to the method described in Example 117.

¹H-NMR (400 MHz, CD₃OD) δ: 8.17 (1H, s), 7.82 (2H, s), 7.47 (1H, d,J=7.1 Hz), 7.18-7.16 (1H, m), 6.66 (1H, d, J=7.6 Hz), 5.75 (2H, s), 2.59(3H, s).

Example 121 Synthesis of3-[1-(2,6-dimethylbenzyl)-3-methyl-1H-indazole-6-yl]propionic acid [121](hereinafter referred to as a compound [121])

(1) Synthesis ofmethyl(E)-3-[1-(2,6-dimethylbenzyl)-3-methyl-1H-indazole-6-yl]acrylate[121-1] (hereinafter referred to as a compound [121-1])

To a solution of the compound [66-1] obtained in the process (1) ofExample 66 (33 mg) in N,N-dimethylformamide (270 μL) were added methylacrylate (18 μL),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloridedichloromethane adduct (9.9 mg), tetrabutylammonium bromide (34 mg) andtriethylamine (28 μL) at room temperature, and then the reaction mixturewas subjected to microwave irradiation at 115° C. for 15 minutes. Aftercooling to room temperature, to the reaction mixture was added 10%aqueous solution of citric acid, and the reaction mixture was extractedwith ethyl acetate. The obtained organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (27 mg)as a yellowish white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.64 (1H, d, J=15.9 Hz), 7.60 (1H, d, J=8.3Hz) 7.27-7.26 (1H, m), 7.21 (1H, t, J=7.3 Hz), 7.10 (2H, d, J=7.6 Hz),6.96 (1H, s), 6.37 (1H, d, J=15.9 Hz), 5.52 (2H, s), 3.81 (3H, s), 2.54(3H, s), 2.33 (6H, s).

ESI-MS found: 335 [M+H]⁺

(2) Synthesis of methyl3-[1-(2,6-dimethylbenzyl)-3-methyl-1H-indazole-6-yl]propionate [121-2](hereinafter referred to as a compound [121-2])

To a solution of the compound [121-1] obtained in the process (1) (21mg) in ethanol (3.0 mL) was added 5% palladium-activated carbon (21 mg)at room temperature, and then the reaction mixture was stirred at roomtemperature for 2 hours under hydrogen atmosphere. The palladium oncarbon was filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (13 mg) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 7.52 (1H, d, J=8.3 Hz), 7.19-7.15 (1H, m),7.08 (2H, d, J=7.6 Hz), 6.91 (1H, d, J=8.1 Hz), 6.75 (1H, s), 5.47 (2H,s), 3.65 (3H, s), 2.96 (2H, t, J=7.8 Hz), 2.58 (2H, t, J=7.8 Hz), 2.51(3H, s) 2.33 (6H, s).

ESI-MS found: 337 [M+H]⁺

(3) Synthesis of3-[1-(2,6-dimethylbenzyl)-3-methyl-1H-indazole-6-yl]propionic acid [121]

The titled compound (13 mg) as a white solid was prepared from thecompound [121-2] obtained in the process (2) (13 mg) according to themethod of the process (2) of Example 117.

¹H-NMR (400 MHz, CDCl₃) δ: 7.52 (1H, d, J=8.3 Hz), 7.19-7.15 (1H, m),7.07 (2H, d, J=7.6 Hz), 6.91 (1H, d, J=8.1 Hz), 6.72 (1H, s), 5.48 (2H,s), 2.97 (2H, t, J=7.7 Hz), 2.62 (2H, t, J=7.7 Hz), 2.51 (3H, s), 2.31(6H, s).

ESI-MS found: 323 [M+H]⁺

Example 122 Synthesis of3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]propionic acid [122](hereinafter referred to as a compound [122])

(1) Synthesis of methyl(E)-3-(3-methyl-1H-indazole-6-yl)acrylate [122-1](hereinafter referred to as a compound [122-1])

To a solution of 6-Bromo-3-methyl-1H-indazole (2.1 g) obtained with themethod described in the document (JP 2009-528363 W) inN,N-dimethylformamide (10 mL) were added methyl acrylate (1.8 mL),palladium acetate (II) (225 mg), tris(2-methylphenyl)phosphine (609 mg)and triethylamine (2.8 mL) at room temperature, and then the reactionmixture was subjected to microwave irradiation at 150° C. for 10minutes. After cooling to room temperature, the reaction mixture wasquenched with water, and extracted with chloroform. The obtained organiclayer was washed with brine, dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive the titled compound (1.8 g) as a yellowish white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 9.91 (1H, br), 7.81 (1H, d, J=15.9 Hz), 7.67(1H, d, J=8.3 Hz), 7.54 (1H, s), 7.36 (1H, d, J=8.3 Hz), 6.52 (1H, d,J=15.9 Hz), 3.83 (3H, s), 2.57 (3H, s).

ESI-MS found: 217 [M+H]⁺

(2) Synthesis of methyl 3-(3-methyl-1H-indazole-6-yl)propionate [122-2](hereinafter referred to as a compound [122-2])

The titled compound (1.5 g) as a white solid was prepared from thecompound [122-1] obtained in the process (1) (1.8 g) according to themethod of the process (2) of Example 121.

¹H-NMR (400 MHz, CDCl₃) δ: 9.72 (1H, br), 7.59 (1H, d, J=8.3 Hz), 7.24(1H, s), 7.00 (1H, d, J=8.1 Hz), 3.67 (3H, s), 3.08 (2H, t, J=7.7 Hz),2.69 (2H, t, J=7.8 Hz), 2.56 (3H, s).

ESI-MS found: 219 [M+H]⁺

(3) Synthesis of methyl3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]propionate [122-3](hereinafter referred to as a compound [122-3])

The titled compound (1.27 g) as a yellowish white solid was preparedfrom the compound [122-2] obtained in the process (2) (871 mg) and2,6-dichlorobenzyl chloride according to the method of the process (1)of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.53 (1H, d, J=8.3 Hz), 7.37 (2H, d, J=8.1Hz) 7.24-7.20 (1H, m), 7.18 (1H, s), 6.95 (1H, d, J=8.3 Hz), 5.69 (2H,s), 3.67 (3H, s), 3.07 (2H, t, J=7.7 Hz), 2.68 (2H, t, J=7.8 Hz), 2.50(3H, s).

ESI-MS found: 337 [M+H]⁺

(4) Synthesis of3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]propionic acid [122]

The titled compound (680 mg) as a yellowish white solid was preparedfrom the compound [122-3] obtained in the process (3) (871 mg) accordingto the method of the process (2) of Example 117.

¹H-NMR (400 MHz, CD₃OD) δ: 7.57 (1H, d, J=8.1 Hz), 7.44 (2H, d, J=8.1Hz), 7.34 (1H, s), 7.33 (1H, t, J=7.2 Hz), 7.02 (1H, d, J=8.3 Hz), 5.70(2H, s), 3.04 (2H, t, J=7.7 Hz), 2.65 (2H, t, J=7.7 Hz), 2.44 (3H, s).

ESI-MS found: 363 [M+H]⁺

Example 123 Synthesis of potassium3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]propionate [123](hereinafter referred to as a compound [123])

To a solution of the compound [122] (24 mg) in ethanol (2.0 mL) wasadded an aqueous solution of 1N-potassium hydroxide (65 μL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (27 mg) as a yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.55 (1H, d, J=8.3 Hz), 7.44 (2H, d, J=8.1Hz), 7.36 (1H, s), 7.36-7.32 (1H, m), 7.05 (1H, d, J=8.3 Hz), 5.71 (2H,s), 3.04 (2H, t, J=8.1 Hz), 2.50 (2H, t, J=8.2 Hz), 2.44 (3H, s).

ESI-MS found: 363 [M+K+2H]⁺

Example 124 Synthesis of3-{1-[(5-chlorobenzo[b]thiophene-3-yl)methyl]-3-methyl-1H-indazole-6-yl}propionicacid [124] (hereinafter referred to as a compound [124])

The titled compound (7.0 mg) was prepared from the compound [122-2]obtained in the process (2) of Example 122 (93 mg) and3-(bromomethyl)-5-chlorobenzo[b]thiophene according to the method of theprocess (5) of Example 102.

¹H-NMR (400 MHz, CDCl₃) δ: 7.85 (1H, s), 7.71 (1H, d, J=8.5 Hz), 7.58(1H, d, J=7.8 Hz), 7.29 (1H, dd, J=8.7, 1.6 Hz), 7.14 (1H, s), 7.13 (1H,s), 6.99 (1H, d, J=8.3 Hz), 5.66 (2H, s), 3.05 (2H, t, J=7.7 Hz), 2.70(2H, t, J=7.7 Hz), 2.58 (3H, s).

ESI-MS found: 385 [M+H]⁺

Example 125 Synthesis of3-[1-(2-chloro-6-cyanobenzyl)-3-methyl-1H-indazole-6-yl]propionic acid[125] (hereinafter referred to as a compound [125])

To a solution of the compound [122] (29.7 mg) in N,N-dimethylformamide(0.8 mL) were added zinc cyanide (4.8 mg),tris(dibenzylideneacetone)dipalladium(0) (3.7 mg) and2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (7.8 mg) at roomtemperature, and then the reaction mixture was subjected to microwaveirradiation at 160° C. for 30 minutes. The reaction mixture was quenchedwith water, and extracted with ethyl acetate, and then the obtainedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by reverse phase preparative liquid chromatography to givethe titled compound (13.3 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.78 (1H, d, J=7.6 Hz), 7.74 (1H, d, J=8.1Hz), 7.59 (1H, d, J=8.3 Hz), 7.54-7.50 (1H, m), 7.45 (1H, s), 7.06 (1H,d, J=8.3 Hz), 5.72 (2H, s), 3.08 (2H, t, J=7.7 Hz), 2.68 (2H, t, J=7.6Hz), 2.44 (3H, s).

ESI-MS found: 354 [M+H]⁺

Example 126 Synthesis of potassium3-[1-(2-chloro-6-cyanobenzyl)-3-methyl-1H-indazole-6-yl]propionate [126](hereinafter referred to as a compound [126])

To a solution of the compound [125] (13.3 mg) in ethanol (1.3 mL) wasadded 1M-potassium hydroxide solution (38 μL) at room temperature, andthe solution was concentrated under reduced pressure to give the titledcompound (10.1 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.78 (1H, d, J=7.8 Hz), 7.74 (1H, d, J=8.3Hz), 7.57 (1H, d, J=8.3 Hz), 7.54-7.50 (1H, m), 7.45 (1H, s), 7.08 (1H,d, J=8.3 Hz), 5.72 (2H, s), 3.06 (2H, t, J=8.1 Hz), 2.52 (2H, t, J=8.1Hz), 2.44 (3H, s).

ESI-MS found: 354 [M+K+2H]⁺

Example 127 Synthesis of3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]-3-hydroxypropionicacid [127] (hereinafter referred to as a compound [127])

(1) Synthesis of 1-(2,6-dichlorobenzyl)-3-methyl-6-vinyl-1H-indazole[127-1] (hereinafter referred to as a compound [127-1])

To a solution of the compound [97-1] obtained in the process (1) ofExample 97 (537 mg) in dimethyl formamide (10 mL) were addedtributylvinyltin (0.5 mL), lithium chloride (204 mg) andbis(triphenylphosphine)palladium(II)dichloride (54 mg) at roomtemperature, and then the reaction mixture was stirred at 120° C. for 2hours. The reaction mixture was quenched with water, and extracted withethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (326 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.55 (1H, d, J=8.3 Hz), 7.46-7.21 (5H, m),6.81 (1H, dd, J=17.4-10.9 Hz), 5.79 (1H, d, J=17.6 Hz), 5.71 (2H, s),5.29 (1H, d, J=11.0 Hz), 2.51 (3H, s).

(2) Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-carbaldehyde [127-2](hereinafter referred to as a compound [127-2])

The titled compound (140 mg) as a yellow solid was prepared from thecompound [127-1] obtained in the process (1) (323 mg) according to themethod of the process (3) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 10.1 (1H, s), 7.92 (1H, s), 7.75 (1H, d,J=8.3 Hz), 7.64 (1H, d, J=8.3 Hz), 7.39 (2H, d, J=8.1 Hz), 7.29-7.25(1H, m), 5.81 (2H, s), 2.56 (3H, s).

(3) Synthesis of3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]-3-hydr oxypropionicacid [127]

To a solution of the compound [127-2] obtained in the process (2) (105mg) in benzene (5 mL) were added zinc powder (40 mg) and ethylbromoacetate (0.1 mL) at room temperature, and then the reaction mixturewas heated at reflux for 2 hours. The reaction mixture was quenched withwater, and extracted with ethyl acetate. The obtained organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give a yellow solid. The obtainedyellow solid was dissolved in ethanol (3 mL), and an aqueous solution of1N-sodium hydroxide (3 mL) was added at room temperature. The reactionmixture was stirred at 60° C. for 2 hours. To the reaction mixture wasadded 1N hydrochloric acid, and the precipitated solid was filtered togive the titled compound (108 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.65 (1H, dd, J=8.3 Hz), 7.57 (1H, s), 7.44(2H, d, J=8.1 Hz), 7.35-7.33 (1H, m), 7.18 (1H, d, J=8.3 Hz), 5.73 (2H,s), 5.24-5.22 (1H, m), 2.74-2.73 (2H, m), 2.46 (3H, s).

Example 128 Synthesis of[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]hydroxyacetic acid[128] (hereinafter referred to as a compound [128])

(1) Synthesis of[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]hydroxyacetonitrile[128-1] (hereinafter referred to as a compound [128-1])

To a solution of the compound [127-2] obtained in the process (2) ofExample 127 (225 mg) in tetrahydrofuran (1 mL) were added trimethylsilylcyanide (875 mL) and zinc iodide (14 mg) at room temperature, and thereaction mixture was stirred at room temperature for 5 days. Thereaction mixture was quenched with water, and extracted with ethylacetate. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure to give a brown oil. The obtained oil was dissolved in methanol(2 mL), and p-toluene sulfonic acid (12 mg) was added at roomtemperature, and the reaction mixture was stirred at room temperaturefor 3 hours. To the reaction mixture was added a saturated aqueoussolution of sodium hydrogen carbonate, and the reaction mixture wasextracted with ethyl acetate. The obtained organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography to give the titled compound (218 mg) as a whitesolid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.70 (1H, d, J=8.3 Hz), 7.56 (1H, s), 7.38(2H, d, J=8.1 Hz), 7.30-7.20 (2H, m), 5.75 (2H, s), 5.66 (1H, d, J=6.6Hz), 2.54 (3H, s), 1.60-1.50 (1H, br).

(2) Synthesis of[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]hydroxyacetic acid[128] (hereinafter referred to as a compound [128])

To a solution of the compound [128-1] obtained in the process (1) (24mg) in acetic acid (1 mL) was added concentrated hydrochloric acid (1mL) at room temperature, and the reaction mixture was stirred at 60° C.for 5 hours. The reaction mixture was quenched with water, and extractedwith ethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by reverse phasepreparative liquid chromatography to give the titled compound (19 mg) asa white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.65 (2H, d, J=9.8 Hz), 7.42 (2H, d, J=8.1Hz), 7.34-7.26 (2H, m), 5.73 (2H, s), 5.29 (1H, s), 2.46 (3H, s).

ESI-MS found: 365 [M+H]⁺

Example 129 Synthesis of potassium[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]hydroxyacetate [129](hereinafter referred to as a compound [129])

To a solution of the compound [128] (19 mg) in ethanol (1 mL) was addedan aqueous solution of 1N-potassium hydroxide (58 mL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (20 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.67 (1H, s), 7.59 (1H, d, J=8.3 Hz), 7.43(2H, d, J=7.8 Hz), 7.36-7.28 (2H, m), 5.71 (2H, s), 4.99 (1H, s), 2.44(3H, s).

ESI-MS found: 365 [M+K+2H]⁺

Example 130 Synthesis of4-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]-4-oxobutyric acid[130] (hereinafter referred to as a compound [130])

(1) Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-6-tributylstannanyl-1H-indazole [130-1](hereinafter referred to as a compound [130-1])

To a solution of the compound [97-1] obtained in the process (1) ofExample 97 (1.12 g) in toluene (30 mL) were added bis(tributyltin) (1.8mL) and tetrakis(triphenylphosphine)palladium(0) (177 mg) at roomtemperature, and then the reaction mixture was heated at reflux for 2hours. The reaction mixture was quenched with water, and extracted withethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (774 mg) as a colorless oil.

¹H-NMR (400-MHz, CDCl₃) δ: 7.59 (1H, d, J=7.8 Hz), 7.37-7.36 (3H, m),7.23-7.21 (1H, m), 7.16 (1H, d, J=7.8 Hz), 5.77 (2H, s), 2.53 (3H, s),1.54-1.48 (6H, m), 1.39-1.28 (12H, m), 0.95-0.87 (9H, m).

(2) Synthesis of ethyl4-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]-4-oxobutyrate[130-2] (hereinafter referred to as a compound [130-2])

To a solution of the compound [130-1] obtained in the process (1) (568mg) in toluene (10 mL) were added ethyl succinyl chloride (0.2 mL) andtetrakis(triphenylphosphine)palladium (0) (62 mg) at room temperature,and then the reaction mixture was heated at reflux for 30 minutes. Thereaction mixture was quenched with water, and extracted with ethylacetate. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (103 mg) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 8.06 (1H, s), 7.73-7.68 (2H, m), 7.39 (2H, d,J=8.1 Hz), 7.28-7.25 (1H, m), 5.79 (2H, s), 4.19 (2H, q, J=7.2 Hz), 3.37(2H, t, J=6.6 Hz), 2.79 (2H, t, J=6.7 Hz), 2.55 (3H, s), 1.29 (3H, t,J=7.2 Hz).

(3) Synthesis of4-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]-4-oxobutyric acid[130]

To a solution of the compound [130-2] obtained in the process (2) (136mg) in methanol (3 mL) was added an aqueous solution of 1N-sodiumhydroxide (3 mL) at room temperature, and then the reaction mixture wasstirred at 60° C. for 2 hours. To the reaction mixture was added1N-hydrochloric acid, and the precipitated solid was filtered to givethe titled compound (119 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 8.25 (1H, s), 7.76 (2H, s), 7.46 (2H, d,J=7.8 Hz), 7.38-7.34 (1H, m), 5.85 (2H, s), 3.39 (2H, t, J=6.5 Hz), 2.72(2H, t, J=6.3 Hz), 2.50 (3H, s).

ESI-MS found: 391 [M+H]⁺

Example 131 Synthesis of2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]acetamide [131](hereinafter referred to as a compound [131])

To a solution of the compound [97] (299 mg) in tetrahydrofuran (5 mL)was added thionyl chloride (0.5 mL) at room temperature, and then thereaction mixture was stirred at 50° C. for 1 hour. The reaction mixturewas concentrated under reduced pressure, and then the obtained residuewas dissolved in tetrahydrofuran (5 mL). To the solution was added 30%ammonia water at 0° C., and the reaction mixture was stirred for 1 hour.To the reaction mixture was added 3N-hydrochloric acid, and extractedwith chloroform. The obtained organic layer was washed with brine, driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (196 mg)as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.61 (1H, d, J=8.1 Hz), 7.47 (1H, s), 7.43(2H, d, J=7.8 Hz), 7.33 (1H, dd, J=8.8, 7.3 Hz), 7.09 (1H, d, J=8.3 Hz),5.72 (2H, s), 4.90-4.80 (2H, brs), 3.65 (2H, s), 2.45 (3H, s).

ESI-MS found: 348 [M+H]⁺

Example 132 Synthesis of3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]propionamide [132](hereinafter referred to as a compound [132])

The titled compound (141.3 mg) as a white solid was prepared from thecompound [122] (198.3 mg) according to the method of Example 131.

¹H-NMR (400 MHz, CDCl₃) δ: 7.54 (1H, d, J=8.3 Hz), 7.36 (2H, d, J=8.1Hz) 7.26-7.20 (2H, m), 6.97 (1H, d, J=8.3 Hz), 5.69 (2H, s), 5.26 (2H,s), 3.09 (2H, t, J=7.6 Hz), 2.57 (2H, t, J=7.6 Hz), 2.50 (3H, s).

ESI-MS found: 362 [M+H]⁺

Example 133 Synthesis of4-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]butyric acid [133](hereinafter referred to as a compound [133])

(1) Synthesis of methyl(E)-4-[3-methyl-1H-indazole-6-yl]-3-butenoate[133-1] (hereinafter referred to as a compound [133-1])

To a solution of 6-bromo-3-methyl-1H-indazole obtained with the methoddescribed in the document (JP 2009-528363 W) (213 mg) inN,N-dimethylformamide (2 mL) were added triethylamine (0.28 mL),palladium acetate (II) (27 mg), tris(2-methylphenyl)phosphine (62 mg)and 3-butenoic acid (0.17 mL), and the reaction mixture was subjected tomicrowave irradiation at 150° C. for 10 minutes. The reaction mixturewas quenched with water, and extracted with ethyl acetate. The obtainedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. To a solution of theobtained residue in tetrahydrofuran (5 mL) was added 0.6Mtetrahydrofuran solution of trimethylsilyl diazomethane (0.17 mL), andthen the reaction mixture was concentrated under reduced pressure, andThe obtained residue was purified by silica gel column chromatography togive the titled compound (90 mg) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 9.90-9.80 (1H, brs), 7.58 (1H, d, J=8.3 Hz),7.33 (1H, s), 7.23 (1H, d, J=8.5 Hz), 6.58 (1H, d, J=15.9 Hz), 6.41-6.33(1H, m), 3.73 (3H, s), 3.28 (2H, d, J=6.6 Hz), 2.57 (3H, s).

(2) Synthesis of methyl 4-[3-methyl-1H-indazole-6-yl]butanoate [133-2](hereinafter referred to as a compound [133-2])

The titled compound (76 mg) as a colorless oil was prepared from thecompound [133-1] obtained in the process (1) (90 mg) according to themethod of the process (2) of Example 121.

¹H-NMR (400 MHz, CDCl₃) δ: 9.78 (1H, brs), 7.58 (1H, d, J=8.3 Hz), 7.21(1H, s), 6.99 (1H, d, J=8.1 Hz), 3.66 (3H, s), 2.78 (2H, t, J=7.6 Hz),2.57 (3H, s), 2.35 (2H, t, J=7.4 Hz), 2.05-1.97 (2H, m).

(3) Synthesis of4-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]butyric acid [133]

The titled compound (61 mg) as a white solid was prepared from thecompound [133-2] obtained in the process (2) (76 mg) and2,6-dichlorobenzyl chloride (98 mg) according to the method of theprocess (5) of Example 102.

¹H-NMR (400 MHz, CD₃OD) δ: 7.58 (1H, d, J=8.3 Hz), 7.44 (2H, d, J=8.1Hz) 7.34-7.32 (1H, m), 7.28 (1H, s), 7.00 (1H, d, J=8.3 Hz), 5.71 (2H,s), 2.78 (2H, t, J=7.6 Hz), 2.45 (3H, s), 2.29 (2H, t, J=7.3 Hz),1.99-1.92 (2H, m).

Example 134 Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-6-(1H-tetrazole-5-ylmethyl)-1H-indazole[134] (hereinafter referred to as a compound [134])

(1) Synthesis of[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]acetonitrile [134-1](hereinafter referred to as a compound [134-1])

To the compound [131] (154 mg) was added thionyl chloride (6.0 mL) atroom temperature, and the reaction mixture was stirred at roomtemperature for 5 minutes. The reaction mixture was cooled to 0° C., andthen an aqueous solution of 3 N-sodium hydroxide was added, and thereaction mixture was extracted with chloroform. The obtained organiclayer was washed with brine, dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive the titled compound (112 mg) as a pale yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.61 (1H, d, J=8.3 Hz), 7.38 (2H, d, J=8.1Hz), 7.34 (1H, s), 7.26-7.23 (1H, m), 7.00 (1H, d, J=8.1 Hz), 5.73 (2H,s), 3.87 (2H, s), 2.52 (3H, s).

ESI-MS found: 330 [M+H]⁺

(2) Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-6-(1H-tetrazole-5-ylmethyl)-1H-indazole[134]

To a solution of the compound [134-1] obtained in the process (1) (112mg) in N,N-dimethylformamide (1.7 mL) were added ammonium chloride (73mg) and sodium azide (66 mg) at room temperature, and then the reactionmixture was subjected to microwave irradiation at 160° C. for 2 hours.After cooling to room temperature, the reaction mixture was added6N-hydrochloric acid, and extracted with ethyl acetate. The obtainedorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (77 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.64 (1H, d, J=8.3 Hz), 7.41 (2H, d, J=7.8Hz), 7.33 (1H, t, J=8.1 Hz), 7.28 (1H, s), 7.05 (1H, d, J=8.3 Hz), 5.70(2H, s), 4.44 (2H, s), 2.46 (3H, s).

ESI-MS found: 373 [M+H]⁺

Example 135 Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-6-[2-(1H-tetrazole-5-yl)ethyl]-1H-indazole[135] (hereinafter referred to as a compound [135])

(1) Synthesis of3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]propionitrile[135-1] (hereinafter referred to as a compound [135-1])

The titled compound (82.4 mg) as a white solid was prepared from thecompound [132] (125.8 mg) according to the method of the process (1) ofExample 134.

¹H-NMR (400 MHz, CDCl₃) δ: 7.58 (1H, d, J=8.1 Hz), 7.37 (2H, d, J=8.1Hz), 7.26-7.23 (2H, m), 6.96 (1H, d, J=8.1 Hz), 5.71 (2H, s), 3.07 (2H,t, J=7.3 Hz), 2.66 (2H, t, J=7.3 Hz), 2.51 (3H, s).

(2) Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-6-[2-(1H-tetrazole-5-yl)ethyl]-1H-indazole[135]

The titled compound (9.2 mg) as a white solid was prepared from thecompound [135-1] obtained in the process (1) (40.7 mg) according to themethod of the process (2) of Example 134.

¹H-NMR (400 MHz, CD₃OD) δ: 7.60 (1H, d, J=8.3 Hz), 7.43 (2H, d, J=7.8Hz), 7.33-7.25 (2H, m), 7.00 (1H, d, J=8.1 Hz), 5.66 (2H, s), 3.31-3.22(4H, m), 2.44 (3H, s).

ESI-MS found: 387 [M+H]⁺

Example 136 Synthesis of5-{[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]methyl}-1,3,4-oxadiazol-2(3H)-one[136] (hereinafter referred to as a compound [136])

(1) Synthesis of tert-butylN′-{2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]acetyl}hydrazinecarboxylate[136-1] (hereinafter referred to as a compound [136-1])

To a solution of the compound [97] (73.2 mg) in chloroform (1.1 mL) wereadded tert-butylcarbazate (222.0 mg), 1-hydroxybenzotriazole monohydrate(113.5 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (161.0 mg) at room temperature, and then the reactionmixture was stirred for 18 hours. The reaction mixture was quenched withwater, and extracted with ethyl acetate. The obtained organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (84.0mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.61 (1H, d, J=8.1 Hz), 7.37 (2H, d, J=8.0Hz), 7.33 (1H, s), 7.23-7.08 (2H, m), 7.04 (1H, d, J=8.1 Hz), 6.39 (1H,s), 5.69 (2H, s), 3.76 (2H, s), 2.50 (3H, s), 1.45 (9H, s).)

(2) Synthesis of[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]acetic acid hydrazide[136-2] (hereinafter referred to as a compound [136-2])

To a solution of the compound [136-1] obtained in the process (1) (84.0mg) in chloroform (0.9 mL) was added trifluoroacetic acid (0.6 mL) atroom temperature, and then the reaction mixture was stirred for 1 hour.The reaction mixture was concentrated under reduced pressure, addedsaturated sodium hydrogen carbonate, and extracted with ethyl acetate.The obtained residue was purified by silica gel column chromatography togive the titled compound (62.7 mg) as a brown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.60 (1H, d, J=8.1 Hz), 7.37 (2H, d, J=8.1Hz), 7.24-7.20 (2H, m), 6.98 (1H, d, J=8.1 Hz), 6.59 (1H, s), 5.70 (2H,s), 3.84 (2H, s), 3.69 (2H, s), 2.51 (3H, s).

(3) Synthesis of5-{[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]methyl}-1,3,4-oxadiazol-2(3H)-one[136]

To a solution of [136-2] obtained in the process (2) (84.0 mg) intetrahydrofuran (1.7 mL) were added N,N-diisopropylethylamine (0.15 mL)and 1,1′-carbonyldiimidazole (84.2 mg) at room temperature, and then thereaction mixture was stirred for 2.5 hours. The reaction mixture wasconcentrated under reduced pressure, and then The obtained residue waspurified by reverse phase preparative liquid chromatography to give thetitled compound (9.2 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.65 (1H, d, J=8.3 Hz), 7.44 (2H, d, J=7.8Hz), 7.36 (1H, s), 7.35-7.32 (1H, m), 7.07 (1H, d, J=8.3 Hz), 5.74 (2H,s), 4.03 (2H, s), 2.47 (3H, s).

ESI-MS found: 389 [M+H]⁺

Example 137 Synthesis of5-{[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]methyl}-1,3,4-oxadiazol-2(3H)-thione[137] (hereinafter referred to as a compound [137])

To a solution of [136-2] obtained in the process (2) of Example 136 (9.1mg) in ethanol (0.4 mL) were added carbon bisulfide (10.6 μL) and anaqueous solution of 1N-potassium hydroxide at room temperature, and thenthe reaction mixture was stirred at 80° C. for 16 hours. To the reactionmixture was added 2N-hydrochloric acid for acidification, and extractedwith ethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by reverse phasepreparative liquid chromatography to give the titled compound (5.8 mg)as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.56 (1H, d, J=8.0 Hz), 7.35 (2H, d, J=7.6Hz), 7.27 (1H, s), 7.26-7.23 (1H, m), 6.98 (1H, d, J=8.4 Hz), 5.64 (2H,s), 4.08 (2H, s), 2.37 (3H, s).

ESI-MS found: 405 [M+H]⁺

Example 138 Synthesis of2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yloxy]acetic acid [138](hereinafter referred to as a compound [138])

(1) Synthesis of 6-methoxy-3-methyl-1H-indazole [138-1] (hereinafterreferred to as a compound [138-1])

To 2′-fluoro-4′-methoxyacetophenone (5.24 g) was added hydrazinemonohydrate (20 mL) at room temperature, and then the reaction mixturewas stirred at 140° C. for 20 hours. The precipitated solid was filteredto give the titled compound (4.20 g) as a red solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.52 (1H, d, J=9.3 Hz), 6.80-6.78 (2H, m),3.86 (3H, s), 2.54 (3H, s).

(2) Synthesis of 1-(2,6-dichlorobenzyl)-6-methoxy-3-methyl-1H-indazole[138-2] (hereinafter referred to as a compound [138-2])

The titled compound (785 mg) as a yellow solid was prepared from thecompound [138-1] obtained in the process (1) (585 mg) according to themethod of the process (1) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.46 (1H, d, J=8.8 Hz), 7.37 (2H, d, J=8.1Hz), 7.25-7.21 (1H, m), 6.74 (1H, dd, J=8.7, 1.8 Hz), 6.69 (1H, s), 5.67(2H, s), 3.81 (3H, s), 2.49 (3H, s).

(3) Synthesis of 1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-ol[138-3] (hereinafter referred to as a compound [138-3])

To a solution of the compound [138-2] obtained in the process (2) (785mg) in dichloromethane (10 mL) was added 1M dichloromethane solution ofboron tribromide (10 mL), and the reaction mixture was stirred at roomtemperature for 10 minutes. The reaction mixture was quenched withwater, and extracted with chloroform. The obtained organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (84 mg)as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.46-7.44 (3H, m), 7.35-7.31 (1H, m), 6.70(1H, s), 6.68-6.65 (1H, m), 5.60 (2H, s), 2.40 (3H, s).

(4) Synthesis of ethyl[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yloxy]acetate [138-4](hereinafter referred to as a compound [138-4])

To a solution of the compound [138-3] obtained in the process (3) (81mg) in dimethyl formamide (3 mL) were added potassium carbonate (78 mg)and ethyl bromoacetate (0.05 mL), and the reaction mixture was stirredat room temperature for 20 hours. The reaction mixture was quenched withwater, and extracted with ethyl acetate. The obtained organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (89 mg)as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.50 (1H, d, J=8.8 Hz), 7.37 (2H, d, J=8.1Hz) 7.24-7.22 (1H, m), 6.81 (1H, dd, J=8.8, 2.0 Hz), 6.67 (1H, d, J=1.7Hz), 5.65 (2H, s), 4.63 (2H, s), 4.28 (2H, q, J=7.2 Hz), 2.48 (3H, s),1.30 (3H, t, J=7.2 Hz).

(5) Synthesis of2-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yloxy]acetic acid [138]

The titled compound (72 mg) as a white solid was prepared from thecompound [138-4] obtained in the process (4) (89 mg) according to themethod of the process (2) of Example 117.

¹H-NMR (400 MHz, CD₃OD) δ: 7.55 (1H, d, J=9.3 Hz), 7.44 (2H, d, J=8.1Hz), 7.36-7.32 (1H, m), 6.83 (2H, d, J=7.1 Hz), 5.68 (2H, s), 4.68 (2H,s), 2.43 (3H, s).

Example 139 Synthesis of[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]methanesulfonic acid[139] (hereinafter referred to as a compound [139])

(1) Synthesis of6-bromomethyl-1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole [139-1](hereinafter referred to as a compound [139-1])

To a solution of the compound [127-2] obtained in the process (2) ofExample 127 (197 mg) in ethanol (10 mL) was added sodium borohydride (32mg), and the reaction mixture was stirred at room temperature for 1hour. The reaction mixture was quenched with water, and extracted withethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. To a solution of the obtained residue indichloromethane (10 mL) were added carbon tetrabromide (304 mg) andtriphenylphosphine (247 mg), and the reaction mixture was stirred atroom temperature for 1 hour. The reaction mixture was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (168 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.59 (1H, d, J=8.3 Hz), 7.40-7.36 (3H, m),7.23 (1H, d, J=8.1 Hz), 7.14 (1H, d, J=8.3 Hz), 5.70 (2H, s), 4.63 (2H,s), 2.50 (3H, s).

(2) Synthesis of[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]methanesulfonic acid[139]

To a solution of the compound [139-1] (119 mg) obtained in the process(1) in dimethyl sulfoxide (2 mL) and water (5 mL) was added sodiumsulfite (49 mg), and the reaction mixture was stirred at 130° C. for 1hour. The reaction mixture was quenched with water, and extracted withchloroform. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (6 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.65-7.63 (2H, brm), 7.45 (2H, d, J=7.8 Hz),7.37-7.33 (1H, m), 7.29 (1H, s), 5.76 (2H, s), 4.22 (2H, s), 2.49 (3H,s).

ESI-MS found: 385 [M+H]⁺

Example 140 Synthesis of2-[1-(2,6-dichlorobenzyl)-3-ethyl-1H-indazole-6-yl]acetic acid [140](hereinafter referred to as a compound [140])

(1) Synthesis of 1-(4-bromo-2-fluorophenyl)propan-1-ol [140-1](hereinafter referred to as a compound [140-1])

To a solution of 4-Bromo-2-fluorobenzaldehyde (5.1 g) in tetrahydrofuran(50 mL) was added 1M tetrahydrofuran solution of ethylmagnesium bromide(41 mL) at 0° C., and then the reaction mixture was stirred at roomtemperature for 1 hour. To the reaction mixture was added a saturatedaqueous solution of ammonium chloride under ice-cooling, and thereaction mixture was extracted with ethyl acetate. The obtained organiclayer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titledcompound (3.78 g) as a colorless liquid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.39-7.16 (3H, m), 4.96-4.85 (1H, m), 1.88(1H, d, J=2.9 Hz), 1.84-1.70 (2H, m), 0.94 (3H, t, J=7.4 Hz).

(2) Synthesis of 1-(4-bromo-2-fluorophenyl)propan-1-one [140-2](hereinafter referred to as a compound [140-2])

To a solution of the compound [140-1] obtained in the process (1) (3.78g) in 1,4-dioxane (50 mL) was added manganese dioxide (10.6 g) at roomtemperature, and then the reaction mixture was stirred at 80° C. for 16hours. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (1.84 g)as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.77 (1H, t, J=8.2 Hz), 7.40-7.30 (2H, m),3.02-2.94 (2H, m), 1.20 (3H, t, J=7.2 Hz).

(3) Synthesis of 6-bromo-3-ethyl-1H-indazole [140-3] (hereinafterreferred to as a compound [140-3])

To a solution of the compound [140-2] obtained in the process (2) (1.84g) in 1,4-dioxane (20 mL) was added hydrazine monohydrate (1.2 mL) atroom temperature, and the reaction mixture was stirred at 110° C. for 17hours. To the reaction mixture was added 0.1N-hydrochloric acid, andthen extracted with ethyl acetate. The obtained organic layer was driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (0.95 g)as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 10.50-9.50 (1H, br), 7.61 (1H, s), 7.57 (1H,d, J=8.5 Hz), 7.28-7.21 (1H, m), 3.00 (2H, q, J=7.6 Hz), 1.41 (3H, t,J=7.6 Hz).

(4) Synthesis of 6-bromo-1-(2,6-dichlorobenzyl)-3-ethyl-1H-indazole[140-4] (hereinafter referred to as a compound [140-4])

The titled compound (295 mg) as a white solid was prepared from thecompound [140-3] (355 mg) obtained in the process (3) and2,6-dichlorobenzyl chloride (610 mg) according to the method of theprocess (1) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.51 (2H, d, J=8.3 Hz), 7.37 (2H, d, J=8.1Hz), 7.23 (1H, d, J=8.3 Hz), 7.18 (1H, d, J=9.8 Hz), 5.68 (2H, s), 2.92(2H, q, J=7.6 Hz), 1.32 (3H, t, J=7.6 Hz).

(5) Synthesis of 6-allyl-1-(2,6-dichlorobenzyl)-3-ethyl-1H-indazole[140-5] (hereinafter referred to as a compound [140-5])

The titled compound (125 mg) as a white solid was prepared from thecompound [140-4] obtained in the process (4) (159 mg) and allyltributyltin (152 μL) according to the method of the process (2) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.57 (1H, d, J=8.3 Hz), 7.35 (2H, d, J=8.1Hz) 7.26-7.18 (1H, m), 7.12 (1H, s), 6.93 (1H, d, J=8.1 Hz), 6.04-5.90(1H, m), 5.70 (2H, s), 5.12-5.05 (2H, m), 3.48 (2H, d, J=6.6 Hz), 2.93(2H, q, J=7.6 Hz), 1.33 (3H, t, J=7.6 Hz).

(6) Synthesis of[1-(2,6-dichlorobenzyl)-3-ethyl-1H-indazole-6-yl]acetaldehyde [140-6](hereinafter referred to as a compound [140-6])

The titled compound (71 mg) as a brown solid was prepared from thecompound [140-5] obtained in the process (5) (125 mg) according to themethod of the process (3) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 9.76 (1H, t, J=2.2 Hz), 7.66 (1H, d, J=8.3Hz), 7.37 (2H, d, J=8.1 Hz), 7.26-7.20 (1H, m), 7.18 (1H, s), 6.94 (1H,d, J=8.1 Hz), 5.72 (2H, s), 3.78 (2H, d, J=2.0 Hz), 2.94 (2H, q, J=7.6Hz), 1.34 (3H, t, J=7.6 Hz).

(7) Synthesis of2-[1-(2,6-dichlorobenzyl)-3-ethyl-1H-indazole-6-yl]acetic acid [140]

The titled compound (56 mg) as a brown solid was prepared from thecompound [140-6] obtained in the process (6) (71 mg) according to themethod of the process (4) of Example 66.

¹H-NMR (400 MHz, CD₃OD) δ: 7.65 (1H, d, J=8.3 Hz), 7.48-7.40 (3H, m),7.34 (1H, dd, J=8.8, 7.3 Hz), 7.07 (1H, d, J=7.6 Hz), 5.73 (2H, s), 3.72(2H, s), 2.90 (2H, q, J=7.6 Hz), 1.30 (3H, t, J=7.7 Hz).

ESI-MS found: 363 [M+H]⁺

Example 141 Synthesis of potassium2-[1-(2,6-dichlorobenzyl)-3-ethyl-1H-indazole-6-yl]acetate [141](hereinafter referred to as a compound [141])

To a solution of the compound [140] (42 mg) in ethanol (1 mL) was addedan aqueous solution of 1N-potassium hydroxide (116 μL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (110 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.60 (1H, d, J=8.1 Hz), 7.46-7.38 (3H, m),7.34-7.30 (1H, m), 7.13 (1H, d, J=8.1 Hz), 5.71 (2H, s), 3.61 (2H, s),2.88 (2H, q, J=7.5 Hz), 1.28 (3H, t, J=7.6 Hz).

ESI-MS found: 363 [M+K+2H]⁺

Example 142 Synthesis of2-[1-(2,6-dimethylbenzyl)-3-ethyl-1H-indazole-6-yl]acetic acid [142](hereinafter referred to as a compound [142])

(1) Synthesis of 6-bromo-1-(2,6-dimethylbenzyl)-3-ethyl-1H-indazole[142-1] (hereinafter referred to as a compound [142-1])

The titled compound (0.80 g) as a white solid was prepared from thecompound [140-3] obtained in the process (3) of Example 140 (1.03 g) and2,6-dimethylbenzyl chloride (1.39 g) according to the method of theprocess (1) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.46 (1H, d, J=8.5 Hz), 7.21-7.08 (5H, m),5.45 (2H, s), 2.93 (2H, q, J=7.6 Hz), 2.32 (6H, s), 1.35 (3H, t, J=7.6Hz).

(2) Synthesis of 6-allyl-1-(2,6-dimethylbenzyl)-3-ethyl-1H-indazole[142-2] (hereinafter referred to as a compound [142-2])

The titled compound (203 mg) as a colorless amorphous substance wasprepared from the compound [142-1] obtained in the process (1) (225 mg)and allyltributyl tin (241 μL) according to the method of the process(2) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.55 (1H, d, J=8.3 Hz), 7.16 (1H, t, J=7.6Hz), 7.06 (2H, d, J=7.6 Hz), 6.89 (1H, d, J=8.3 Hz), 6.71 (1H, s),5.95-5.82 (1H, m), 5.49 (2H, s), 5.10-5.00 (2H, m), 3.37 (2H, d, J=6.8Hz), 2.93 (2H, q, J=7.6 Hz), 2.33 (6H, s), 1.35 (3H, t, J=7.6 Hz).

(3) 1-(2,6-dimethylbenzyl)-3-ethyl-1H-indazole-6-carbaldehyde [142-3A](hereinafter referred to as a compound [142-3A]) and[1-(2,6-dimethylbenzyl)-3-ethyl-1H-indazole-6-yl]acetaldehyde [142-3B](hereinafter referred to as a compound [142-3B])

The titled compound [142-3A] (37 mg) as a white solid was prepared fromthe compound [142-2] (225 mg) obtained in the process (2) according tothe method of the process (3) of Example 66. In addition, the titledcompound [142-3B] (51 mg) as a white solid was obtained.

[142-3A]

¹H-NMR (400 MHz, CDCl₃) δ: 9.91 (1H, s), 7.76 (1H, d, J=8.3 Hz), 7.58(1H, d, J=8.3 Hz), 7.38 (1H, s), 7.23-7.19 (1H, m), 7.11 (2H, d, J=7.6Hz), 5.61 (2H, s), 2.99 (2H, q, J=7.6 Hz), 2.34 (6H, s), 1.38 (3H, t,J=7.6 Hz).

[142-3B]

¹H-NMR (400 MHz, CDCl₃) δ: 9.67 (1H, s), 7.64 (1H, d, J=8.3 Hz)7.20-7.16 (1H, m), 7.08 (2H, d, J=7.6 Hz), 6.88 (1H, d, J=7.8 Hz), 6.70(1H, s), 5.51 (2H, s), 3.66 (2H, d, J=2.0 Hz), 2.96 (2H, q, J=7.6 Hz),2.32 (6H, s), 1.36 (3H, t, J=7.6 Hz).

(4) Synthesis of2-[1-(2,6-dimethylbenzyl)-3-ethyl-1H-indazole-6-yl]acetic acid [142]

The titled compound (35 mg) as a white solid was prepared from thecompound [142-3B] obtained in the process (3) (51 mg) according to themethod of the process (4) of Example 66.

¹H-NMR (400 MHz, CD₃OD) δ: 7.64 (1H, d, J=8.3 Hz), 7.17-7.00 (5H, m),5.50 (2H, s), 3.64 (2H, s), 2.92 (2H, q, J=7.6 Hz), 2.27 (6H, s), 1.31(3H, t, J=7.6 Hz).

ESI-MS found: 323 [M+H]⁺

Example 143 Synthesis of1-(2,6-dimethylbenzyl)-3-ethyl-1H-indazole-6-carboxylic acid [143](hereinafter referred to as a compound [143])

The titled compound (25 mg) as a white solid was prepared from thecompound [142-3A] obtained in the process (3) of Example 142 (37 mg)according to the method of the process (4) of Example 66.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.21 (1H, s), 7.80 (1H, d, J=8.3 Hz), 7.63(1H, d, J=8.5 Hz), 7.14-7.03 (3H, m), 5.56 (2H, s), 2.87 (2H, q, J=7.5Hz), 2.29 (6H, s), 1.24 (3H, t, J=7.6 Hz).

ESI-MS found: 309 [M+H]⁺

Example 144 Synthesis of1-(2,6-dichlorobenzyl)-3-ethyl-1H-indazole-6-carboxylic acid [144](hereinafter referred to as a compound [144])

To the compound [140-4] obtained in the process (4) of Example 140 (34mg) were added water (2 mL), pyridine (32 μL), molybdenum hexacarbonyl(25 mg), 1,1′-bis(diphenylphosphino)ferrocene (9 mg) and palladiumacetate (II) (2 mg) at room temperature, and then the reaction mixturewas subjected to microwave irradiation at 160° C. for 20 minutes. Thereaction mixture was quenched with water, and extracted with ethylacetate. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by reverse phase preparativeliquid chromatography to give the titled compound (5 mg) as a whitesolid.

¹H-NMR (400 MHz, CD₃OD) δ: 8.25 (1H, s), 7.79-7.75 (2H, m), 7.45 (2H, d,J=8.1 Hz), 7.35 (1H, t, J=8.1 Hz), 5.82 (2H, s), 2.94 (2H, q, J=7.6 Hz),1.31 (3H, t, J=7.6 Hz).

ESI-MS found: 349 [M+H]⁺

Example 145 Synthesis of3-[1-(2,6-dichlorobenzyl)-3-ethyl-1H-indazole-6-yl]propionic acid [145](hereinafter referred to as a compound [145])

(1) Synthesis ofmethyl(E)-3-[1-(2,6-dichlorobenzyl)-3-ethyl-1H-indazole-6-yl]acrylate[145-1] (hereinafter referred to as a compound [145-1])

The titled compound (132 mg) as a white solid was prepared from thecompound [140-4] obtained in the process (4) of Example 140 (201 mg) andmethyl acrylate (94 μL) according to the method of the process (1) ofExample 121.

¹H-NMR (400 MHz, CDCl₃) δ: 7.77 (1H, d, J=16.1 Hz), 7.65 (1H, d, J=8.5Hz) 7.44-7.34 (3H, m), 7.33-7.20 (2H, m), 6.47 (1H, d, J=16.1 Hz), 5.76(2H, s), 3.83 (3H, s), 2.95 (2H, q, J=7.6 Hz), 1.34 (3H, t, J=7.6 Hz).

(2) Synthesis of methyl3-[1-(2,6-dichlorobenzyl)-3-ethyl-1H-indazole-6-yl]propionate [145-2](hereinafter referred to as a compound [145-2])

The compound [145-1] obtained in the process (1) (43 mg) was dissolvedin a mixed solvent of ethyl acetate (2 mL) and tetrahydrofuran (2 mL).To the solution were added phenyl sulfide (2 μL) and 5% palladium oncarbon (48 mg), and then the reaction mixture was stirred at roomtemperature for 24 hours under hydrogen atmosphere. The reaction mixturewas filtered, and the filtrate was concentrated under reduced pressure.The obtained residue was purified by preparative thin layerchromatography to give the titled compound (5 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.57 (1H, d, J=8.3 Hz), 7.36 (2H, d, J=7.8Hz) 7.30-7.18 (1H, m), 7.14 (1H, s), 6.94 (1H, d, J=8.3 Hz), 5.70 (2H,s), 3.67 (3H, s), 3.05 (2H, t, J=7.8 Hz), 2.92 (2H, q, J=7.6 Hz), 2.66(2H, t, J=7.7 Hz), 1.31 (3H, t, J=7.6 Hz).

(3) Synthesis of3-[1-(2,6-dichlorobenzyl)-3-ethyl-1H-indazole-6-yl]propionic acid [145]

The titled compound (39 mg) as a white solid was prepared from thecompound [145-2] obtained in the process (2) (40 mg) according to themethod as described in the process (2) of Example 117.

¹H-NMR (400 MHz, CD₃OD) δ: 7.62 (1H, d, J=8.1 Hz), 7.44 (2H, d, J=8.1Hz), 7.35 (1H, d, J=7.6 Hz), 7.31 (1H, s), 7.02 (1H, d, J=8.1 Hz), 5.72(2H, s), 3.04 (2H, t, J=7.6 Hz), 2.89 (2H, q, J=7.6 Hz), 2.65 (2H, t,J=7, 7 Hz), 1.29 (3H, t, J=7.6 Hz).

ESI-MS found: 377 [M+H]⁺

Example 146 Synthesis of(E)-3-[1-(2,6-dichlorobenzyl)-3-ethyl-1H-indazole-6-yl]acrylic acid[146] (hereinafter referred to as a compound [146])

The titled compound (16 mg) as a white solid was prepared from thecompound [145-1] obtained in the process (1) of Example 145 (21 mg)according to the method of the process (2) of Example 117.

¹H-NMR (400 MHz, CD₃OD) δ: 7.85-7.65 (3H, m), 7.50-7.30 (4H, m), 6.55(1H, d, J=16.1 Hz), 5.80 (2H, s), 2.92 (2H, q, J=7.6 Hz), 1.31 (3H, t,J=7.7 Hz).

ESI-MS found: 375 [M+H]⁺

Example 147 Synthesis of2-[1-(2,6-dimethylbenzyl)-3-isopropyl-1H-indazole-6-yl]acetic acid [147](hereinafter referred to as a compound [147])

(1) Synthesis of 6-bromo-3-isopropyl-1H-indazole [147-1] (hereinafterreferred to as a compound [147-1])

The titled compound (300 mg) as a white solid was prepared from4-bromo-2-fluorobenzaldehyde (3.05 g) and 1 M tetrahydrofuran solution(25 mL) of isopropyl magnesium chloride according to the methods of theprocesses (1) to (3) of Example 140.

¹H-NMR (400 MHz, CDCl₃) δ: 7.64-7.61 (2H, m), 7.24 (1H, dd, J=8.5, 1.7Hz), 3.45-3.35 (1H, m), 1.45 (6H, d, J=6.8 Hz).

(2) Synthesis of 6-bromo-1-(2,6-dimethylbenzyl)-3-isopropyl-1H-indazole[147-2] (hereinafter referred to as a compound [147-2])

The titled compound (263 mg) as a white solid was prepared from thecompound [147-1] obtained in the process (1) (300 mg) and2,6-dimethylbenzyl chloride (292 mg) according to the method of theprocess (1) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.56 (1H, dd, J=8.5, 0.5 Hz), 7.21-7.17 (1H,m), 7.12-7.02 (4H, m), 5.48 (2H, s), 3.39-3.28 (1H, m), 2.33 (6H, s),1.41 (6H, d, J=7.1 Hz).

(3) Synthesis of2-[1-(2,6-dimethylbenzyl)-3-isopropyl-1H-indazole-6-yl]acetic acid [147]

The titled compound (41 mg) as a white solid was prepared from thecompound [147-2] obtained in the process (2) (50 mg) according to themethods of the processes (2) to (4) of Example 66.

¹H-NMR (400 MHz, CD₃OD) δ: 7.69 (1H, dd, J=8.4, 0.6 Hz), 7.14-7.11 (1H,m), 7.06-7.04 (3H, m), 7.00 (1H, dd, J=8.3, 1.5 Hz), 5.50 (2H, s), 3.61(2H, s), 3.38-3.29 (1H, m), 2.28 (6H, s), 1.39 (6H, d, J=6.8 Hz).

ESI-MS found: 337 [M+H]⁺

Example 148 Synthesis of2-[3-cyclopropyl-1-(2,6-dichlorobenzyl)-1H-indazole-6-yl]acetic acid[148] (hereinafter referred to as a compound [148])

(1) Synthesis of (4-bromo-2-fluorophenyl)cyclopropyl methanone [148-1](hereinafter referred to as a compound [148-1])

To magnesium (265 mg), tetrahydrofuran (2 mL) was added, and cyclopropylbromide (1.1 mL) was added slowly at room temperature, and then thereaction mixture was stirred at room temperature for 1 hour. To asolution of 4-bromo-2-fluorobenzaldehyde (2.0 g) in tetrahydrofuran (20mL) was added the solution of the obtained Grignard reagent intetrahydrofuran at 0° C., and then the reaction mixture was stirred atroom temperature for 2 days. To the reaction mixture was added asaturated aqueous solution of ammonium chloride, and the reactionmixture was extracted with ethyl acetate. The obtained organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (2.19 g)as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 7.70-7.35 (1H, m), 7.40-7.20 (2H, m),2.60-2.50 (1H, m), 1.43-1.25 (2H, m), 1.11-1.05 (2H, m).

(2) Synthesis of 6-bromo-3-cyclopropyl-1H-indazole [148-2] (hereinafterreferred to as a compound [148-2])

The titled compound (483 mg) as a yellow solid was prepared from thecompound [148-1] obtained in the process (1) (806 mg) according to themethod of the process (3) of Example 140.

¹H-NMR (400 MHz, CDCl₃) δ: 10.0-9.50 (1H, br), 7.65-7.55 (2H, m), 7.23(1H, d, J=8.5, 1.2 Hz), 2.24-2.16 (1H, m), 1.10-1.00 (4H, m).

(3) Synthesis of6-bromo-3-cyclopropyl-1-(2,6-dichlorobenzyl)-1H-indazole [148-3](hereinafter referred to as a compound [148-3])

The titled compound (299 mg) as a white solid was prepared from thecompound [148-2] obtained in the process (2) (200 mg) and2,6-dichlorobenzyl chloride (250 mg) according to the method of theprocess (1) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 7.51-7.49 (2H, m), 7.40-7.30 (2H, m),7.27-7.10 (2H, m), 5.63 (2H, s), 2.16-2.08 (1H, m), 1.10-0.99 (4H, m).

(4) Synthesis of2-[3-cyclopropyl-1-(2,6-dichlorobenzyl)-1H-indazole-6-yl]acetic acid[148]

The titled compound (28 mg) as a brown solid was prepared from thecompound [148-3] obtained in the process (3) (286 mg) according to themethods of the processes (2) to (4) of Example 66.

¹H-NMR (400 MHz, CD₃OD) δ: 7.58 (1H, d, J=7.3 Hz), 7.45-7.36 (3H, m),7.31 (1H, dd, J=8.8, 7.6 Hz), 7.10 (1H, d, J=7.3 Hz), 5.67 (2H, s), 3.59(2H, s), 2.17-2.11 (1H, m), 0.94 (4H, d, J=5.4 Hz).

ESI-MS found: 375 [M+H]⁺

Example 149 Synthesis of3-chloro-1-(2,6-dimethylbenzyl)-1H-indazole-6-carboxylic acid [149](hereinafter referred to as a compound [149])

(1) Synthesis of 2,6-dimethyl benzyl3-chloro-1-(2,6-dimethylbenzyl)-1H-indazole-6-carboxylate [149-1](hereinafter referred to as a compound [149-1])

To a solution of 1H-indazole-6-carboxylic acid (343 mg) in acetonitrile(10 mL) was added N-chlorosuccinimide (313 mg), and the reaction mixturewas stirred at 60° C. for 2 hours. The reaction mixture was concentratedunder reduced pressure, and then acetone (10 mL), potassium carbonate(883 mg) and 2,6-dimethylbenzyl chloride (724 mg) were added and thereaction mixture was stirred at room temperature for 2 days. Thereaction mixture was quenched with water, and extracted with ethylacetate. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (195 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.79 (1H, d, J=8.8 Hz), 7.65 (2H, d, J=8.1Hz) 7.26-7.23 (1H, m), 7.14 (2H, d, J=7.6 Hz), 7.06-7.02 (1H, m), 6.92(2H, d, J=7.6 Hz), 5.54 (2H, s), 5.40 (2H, s), 2.42 (6H, s), 2.25 (6H,s).

(2) Synthesis of3-chloro-1-(2,6-dimethylbenzyl)-1H-indazole-6-carboxylic acid [149](hereinafter referred to as a compound [149])

The titled compound (15 mg) as a white solid was prepared from thecompound [149-1] obtained in the process (1) (24 mg) according to themethod of the process (2) of Example 117.

¹H-NMR (400 MHz, CD₃OD) δ: 8.19 (1H, s), 7.84 (1H, d, J=7.8 Hz), 7.71(1H, d, J=8.5 Hz), 7.18-7.14 (1H, m), 7.08 (2H, d, J=7.3 Hz), 5.64 (2H,s), 2.31 (6H, s).

ESI-MS found: 315 [M+H]⁺

Example 150 Synthesis of3-cyano-1-(2,6-dichlorobenzyl)-1H-indazole-6-carboxylic acid [150](hereinafter referred to as a compound [150])

(1) Synthesis of (2-amino-4-bromophenyl)acetonitrile [150-1](hereinafter referred to as a compound [150-1])

To a solution of ethyl cyanoacetate (3.2 mL) in dimethyl sulfoxide (20mL) was added sodium hydride (1.22 g) at room temperature, and then1,4-dibromo-2-nitrobenzene (4.21 g) was added, and the reaction mixturewas stirred at 90° C. for 3 hours. To the reaction mixture was added asaturated aqueous solution of ammonium chloride, and the reactionmixture was extracted with ethyl acetate. The obtained organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was suspendedin an aqueous solution of 1M-sodium hydrogen carbonate (60 mL), and thereaction mixture was stirred at 80° C. for 24 hours. To the reactionmixture was added 2N-hydrochloric acid, and the reaction mixture wasextracted with ethyl acetate. The obtained organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The obtained residue was dissolved intetrahydrofuran (20 mL), ethanol (40 mL) and water (20 mL). To thesolution were added ammonium chloride (4.03 g) and iron powder (4.22 g),and the reaction mixture was stirred at 100° C. for 5 hours. Thereaction mixture was filtered through a cotton plug, and then thefiltrate was extracted with ethyl acetate. The obtained organic layerwas dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (3.03 g)as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.06 (1H, d, J=8.1 Hz), 6.94-6.91 (2H, m),3.75 (2H, brs), 3.52 (2H, s).

(2) Synthesis of 6-bromo-1H-indazole-3-carbonitrile [150-2] (hereinafterreferred to as a compound [150-2])

To a solution of the compound [150-1] obtained in the process (1) (3.03g) in 2N-hydrochloric acid (50 mL) was added sodium nitrite (1.61 g) atroom temperature, and then the reaction mixture was stirred at roomtemperature for 20 hours. The precipitated solid was filtered, and theobtained solid was dissolved in acetic acid (15 mL). The reactionmixture was stirred at 100° C. for 2 hours. The reaction mixture waspoured into ice water, an aqueous solution of 3N-sodium hydroxide wasadded. The reaction mixture was extracted with ethyl acetate. Theobtained organic layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive the titled compound (1.55 g) as a yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.91 (1H, s), 7.76 (1H, d, J=8.8 Hz), 7.49(1H, d, J=8.8 Hz).

(3) Synthesis of 3-cyano-1-(2,6-dichlorobenzyl)-1H-indazole-6-carboxylicacid [150]

The titled compound (118 mg) as a white solid was prepared from thecompound [150-2] obtained in the process (2) (570 mg) and2,6-dichlorobenzyl chloride (747 mg) according to the method of Example66.

¹H-NMR (400 MHz, DMSO-d₆) δ: 13.31 (1H, brs), 8.67 (1H, s), 7.97 (1H, d,J=8.5 Hz), 7.92 (1H, d, J=8.5 Hz), 7.55 (2H, d, J=7.8 Hz), 7.48-7.44(1H, m), 6.04 (2H, s).

Example 151 Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylicacid [151] (hereinafter referred to as a compound [151])

(1) Synthesis of 2,6-dichloro-N-methoxy-N-methylnicotinamide [151-1](hereinafter referred to as a compound [151-1])

To a suspension of 2,6-dichloronicotinic acid (1.92 g),N,O-dimethylhydroxylamine hydrochloride (1.46 g) and triethylamine (2.1mL) in N,N-dimethylformamide (30 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g),and then the reaction mixture was stirred at room temperature for 4days. The reaction mixture was diluted with ethyl acetate, washed with5% aqueous solution of potassium hydrogen sulfate and a saturatedaqueous solution of sodium hydrogen carbonate and brine. The obtainedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titledcompound (1.61 g) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.65 (1H, d, J=8.0 Hz), 7.34 (1H, d, J=8.0Hz), 3.51 (3H, s), 3.40 (3H, s).

ESI-MS found: 235 [M+H]⁺

(2) Synthesis of 1-(2,6-dichloropyridine-3-yl)ethanone [151-2](hereinafter referred to as a compound [151-2])

To a solution of the compound [151-1] obtained in the process (1) (487mg) in tetrahydrofuran (10 mL) was added 2M diethyl ether solution ofmethylmagnesium iodide (1.24 mL) at 0° C., and then the reaction mixturewas stirred at 70° C. for 72 hours. To the reaction mixture was added anaqueous solution of ammonium chloride, and the reaction mixture wasextracted with ethyl acetate. The obtained organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography to give the titled compound (205 mg) as acolorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 7.93 (1H, d, J=8.1 Hz), 7.37 (1H, d, J=8.1Hz), 2.71 (3H, s).

ESI-MS found: 190 [M+H]⁺

(3) Synthesis of 6-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine [151-3](hereinafter referred to as a compound [151-3])

To a solution of the compound [151-2] obtained in the process (2) (205mg) in dichloromethane (2.7 mL) was added titanium tetraisopropoxide(0.63 mL) at room temperature, and then the reaction mixture was stirredat room temperature for 15 minutes. Next, to the reaction mixture wasadded hydrazine monohydrate (0.11 mL), and stirred at room temperaturefor 3 hours. The reaction mixture was quenched with water, and stirredfor 30 minutes, and then the insoluble materials were separated byfiltration, and the insoluble materials were washed with chloroform. Thefiltrate was concentrated under reduced pressure to give a white solid.To the obtained solid, ethanol (1.5 mL) was added and the reactionmixture was subjected to microwave irradiation at 150° C. for 20minutes. The reaction mixture was quenched with water, and extractedwith ethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (86 mg) as a white solid.

¹H-NMR (400-MHz, CD₃OD) δ: 10.15 (1H, brs), 7.97 (1H, d, J=8.3 Hz), 7.15(1H, d, J=8.3 Hz), and 2.58 (3H, s).

ESI-MS found: 168 [M+H]⁺

(4) Synthesis of6-chloro-1-(2,6-dichlorobenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine[151-4] (hereinafter referred to as a compound [151-4])

The titled compound (104 mg) as a white solid was prepared from thecompound [151-3] obtained in the process (3) (86 mg) and2,6-dichlorobenzyl chloride (208 mg) according to the method of theprocess (1) of Example 66.

¹H-NMR (400-MHz, CDCl₃) ?: 7.89 (1H, d, J=8.3 Hz), 7.39-7.31 (2H, m),7.26-7.18 (1H, m), 7.09 (1H, d, J=8.3 Hz), 5.83 (2H, s), 2.47 (3H, s).

ESI-MS found: 326 [M+H]⁺

(5) Synthesis of1-(2,6-dimethylbenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carbonitrile[151-5] (hereinafter referred to as a compound [151-5])

The compound [151-4] obtained in the process (4) (66 mg), zinc powder (4mg), zinc cyanide (18 mg) and a solution of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (18 mg) inN,N-dimethylformamide (2 mL) were subjected to microwave irradiation at150° C. for 10 minutes under argon atmosphere. The reaction mixture wasquenched with water, and extracted with ethyl acetate. The obtainedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titledcompound (38 mg) as a white solid.

¹H-NMR (400-MHz, CDCl₃) ?: 8.09 (1H, d, J=8.1 Hz), 7.46 (1H, d, J=8.1Hz), 7.37 (2H, d, J=8.1 Hz), 7.25 (1H, d, J=8.3 Hz), 5.90 (2H, s), 2.53(3H, s).

ESI-MS found: 317 [M+H]⁺

(6) Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylicacid [151]

To a solution of the compound [151-5] obtained in the process (5) (38mg) in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) was added3N-sodium hydroxide solution (0.6 mL), and then the reaction mixture wassubjected to microwave irradiation at 150° C. for 5 minutes. To thereaction mixture, 1M hydrochloric acid (0.46 mL) was added, and thesolvent was concentrated under reduced pressure. The obtained residuewas purified by reverse phase preparative liquid chromatography to givethe titled compound (34 mg) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 13.42 (1H, s), 8.37 (1H, d, J=8.3 Hz), 7.86(1H, d, J=8.3 Hz), 7.52 (1H, d, J=8.7 Hz), 7.52 (1H, d, J=7.4 Hz), 7.42(1H, dd, J=8.7, 7.4 Hz), 5.82 (2H, s), 2.44 (3H, s).

ESI-MS found: 336 [M+H]⁺

Example 152 Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-6-(1H-tetrazole-5-ylmethyl)-1H-pyrazolo[3,4-b]pyridine[152] (hereinafter referred to as a compound [152])

(1) Synthesis of[1-(2,6-dichlorobenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-yl]acetonitrile[152-1] (hereinafter referred to as a compound [152-1])

To a solution of the compound [151-4] obtained in the process (4) ofExample 151 (33 mg) in toluene (1.0 mL) was added acetonitrile (52 μL)under argon atmosphere, and then the reaction mixture was cooled to 0°C. Subsequently, 1.0M tetrahydrofuran solution (2.0 mL) of sodiumhexamethyldisilazane was dropped, and the reaction mixture was stirredat 0° C. for 1 hour. To the reaction mixture was added a saturatedaqueous solution of ammonium chloride, and the reaction mixture wasextracted with ethyl acetate. The obtained organic layer was washed withbrine, dried over anhydrous sodium sulfate, filtered, and the filtratewas concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography to give the titled compound(16 mg) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.98 (1H, d, J=8.1 Hz), 7.35 (2H, d, J=7.8Hz), 7.24-7.20 (1H, m), 7.17 (1H, d, J=8.1 Hz), 5.86 (2H, s), 4.04 (2H,s), 2.50 (3H, s).

ESI-MS found: 331 [M+H]⁺

(2) Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-6-(1H-tetrazole-5-ylmethyl)-1H-pyrazolo[3,4-b]pyridine[152]

The titled compound (4.4 mg) as a yellowish white solid was preparedfrom the compound [152-1] obtained in the process (1) (28 mg) accordingto the method of the process (2) of Example 134.

¹H-NMR (400 MHz, CD₃OD) δ: 8.11 (1H, d, J=8.0 Hz), 7.37 (2H, d, J=7.6Hz), 7.29 (1H, dd, J=8.8, 7.1 Hz), 7.21 (1H, d, J=8.3 Hz), 5.79 (2H, s),4.64 (2H, s), 2.45 (3H, s).

ESI-MS found: 374 [M+H]⁺

Example 153 Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylicacid [153] (hereinafter referred to as a compound [153])

(1) Synthesis of 1-(5-bromo-3-fluoropyridine-2-yl)ethanone [153-1](hereinafter referred to as a compound [153-1])

To a solution of 5-bromo-3-fluoropyridin-2-carbonitrile (2.2 g) obtainedby the method described in the document (Journal of Organic Chemistry,2009, Vol. 74, p. 4547) in toluene (22 mL) was added 3.0Mtetrahydrofuran solution (5.4 mL) of methylmagnesium chloride at roomtemperature and the reaction mixture was stirred for 20 minutes. Thereaction mixture was quenched with water, and extracted with chloroform.The obtained organic layer was washed with brine, dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (793 mg) as a pale yellowoil.

¹H-NMR (400 MHz, CDCl₃) δ: 8.56 (1H, s), 7.74 (1H, d, J=9.6 Hz), 2.68(3H, s).

(2) Synthesis of 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine [153-2](hereinafter referred to as a compound [153-2])

To a solution of the compound [153-1] obtained in the process (1) (1.2g) in ethylene glycol (11 mL) was added hydrazine monohydrate (11 mL) atroom temperature, and then the reaction mixture was stirred at 140° C.for 17 hours. After cooling to room temperature, to the reaction mixturewas added water, and the precipitated solid was filtered to give thetitled compound (788 mg) as a yellow crystal.

¹H-NMR (400 MHz, CD₃OD) δ: 8.51 (1H, d, J=1.7 Hz), 8.16 (1H, d, J=2.0Hz), 2.59 (3H, s).

ESI-MS found: 212 [M+H]⁺

(3) Synthesis of6-bromo-1-(2,6-dichlorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine[153-3] (hereinafter referred to as a compound [153-3])

The titled compound (274 mg) as a white solid was prepared from thecompound [153-2] obtained in the process (2) (196 mg) and2,6-dichlorobenzyl chloride according to the method of the process (1)of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 8.51 (1H, d, J=1.7 Hz), 7.80 (1H, d, J=1.7Hz), 7.39 (2H, d, J=7.8 Hz), 7.29-7.26 (1H, m), 5.69 (2H, s), 2.60 (3H,s).

ESI-MS found: 370 [M+H]⁺

(4) Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile[153-4] (hereinafter referred to as a compound [153-4])

To a solution of the compound [153-3] obtained in the process (3) (100mg) in N,N-dimethylformamide (1.3 mL) were added zinc cyanide (25 mg)and tetrakis(triphenylphosphine)palladium(0) (34 mg) at roomtemperature, and then the reaction mixture was subjected to microwaveirradiation at 95° C. for 3 hours. After cooling to room temperature, tothe reaction mixture was added a saturated aqueous solution of potassiumcarbonate, and extracted with ethyl acetate. The obtained organic layerwas washed with brine, dried over anhydrous sodium sulfate, filtered,and the filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography to give thetitled compound (44 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.69 (1H, d, J=1.5 Hz), 7.93 (1H, d, J=1.5Hz), 7.41 (2H, d, J=8.1 Hz), 7.33-7.29 (1H, m), 5.80 (2H, s), 2.65 (3H,s).

(5) Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylicacid [153] (hereinafter referred to as a compound [153])

To a solution of the compound [153-4] obtained in the process (4) (44mg) in ethanol (3.5 mL) was added an aqueous solution of 3N-sodiumhydroxide (3.5 mL) at room temperature, and then the reaction mixturewas stirred at 110° C. for 15 minutes. After cooling to roomtemperature, to the reaction mixture was added 3N-hydrochloric acid, andextracted with chloroform. The obtained organic layer was washed withbrine, dried over anhydrous sodium sulfate, filtered, and the filtratewas concentrated under reduced pressure. The obtained residue waspurified by reverse phase preparative liquid chromatography to give thetitled compound (28 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 9.05 (1H, s), 8.64 (1H, s), 7.46 (2H, d,J=7.8 Hz), 7.38-7.34 (1H, m), 5.87 (2H, s), 2.56 (3H, s).

ESI-MS found: 336 [M+H]⁺

Example 154 Synthesis of potassium1-(2,6-dichlorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate[154] (hereinafter referred to as a compound [154])

To a solution of the compound [153] (22 mg) in ethanol (2.0 mL) wasadded an aqueous solution of 1N-potassium hydroxide (66 μL) at roomtemperature, and the solution was concentrated under reduced pressure,whereby to give the titled compound (25 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 9.06 (1H, s), 8.55 (1H, s), 7.44 (2H, d,J=7.8 Hz), 7.36-7.32 (1H, m), 5.83 (2H, s), 2.54 (3H, s).

ESI-MS found: 336 [M+H]⁺

Example 155 Synthesis of(E)-3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-yl]acrylicacid [155] (hereinafter referred to as a compound [155])

(1) Synthesis ofmethyl(E)-3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-yl]acrylate[155-1] (hereinafter referred to as a compound [155-1])

The titled compound (89 mg) as a white solid was prepared from thecompound [153-3] obtained in the process (3) of Example 153 (100 mg)according to the method of the process (1) of Example 121.

¹H-NMR (400 MHz, CDCl₃) δ: 8.68 (1H, s), 7.79 (1H, d, J=16.1 Hz), 7.70(1H, s), 7.41 (2H, d, J=8.1 Hz), 7.31-7.26 (1H, m), 6.55 (1H, d, J=16.1Hz), 5.77 (2H, s), 3.84 (3H, s), 2.63 (3H, s).

ESI-MS found: 376 [M+H]⁺

(2) Synthesis of(E)-3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-yl]acrylicacid [155]

The titled compound (9.0 mg) as a white solid was prepared from thecompound [155-1] obtained in the process (1) (25 mg) according to themethod of the process (2) of Example 117.

¹H-NMR (400 MHz, CDCl₃) δ: 8.65 (1H, s), 7.76 (1H, d, J=16.3 Hz), 7.71(1H, s), 7.39 (2H, d, J=8.1 Hz), 7.29-7.26 (1H, m), 6.52 (1H, d, J=15.9Hz), 5.76 (2H, s), 2.61 (3H, s).

ESI-MS found: 362 [M+H]⁺

Example 156 Synthesis of1-(2,6-dichlorobenzyl)-3-methyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine[156] (hereinafter referred to as a compound [156])

The titled compound (14 mg) as a white solid was prepared from thecompound [153-4] obtained in the process (4) of Example 153 (71 mg)according to the method of the process (2) of Example 134.

¹H-NMR (400 MHz, CD₃OD) δ: 9.14 (1H, d, J=1.5 Hz), 8.74 (1H, d, J=1.5Hz), 7.47 (2H, d, J=8.1 Hz), 7.37 (1H, dd, J=8.8, 7.3 Hz), 5.89 (2H, s),2.58 (3H, s).

ESI-MS found: 360 [M+H]⁺

Example 157 Synthesis of potassium5-[1-(2,6-dichlorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-yl]-1H-tetrazole-1-ide[157] (hereinafter referred to as a compound [157])

To a solution of the compound [156] (30 mg) in ethanol (2.0 mL) wasadded an aqueous solution of 1N-potassium hydroxide (84 μL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (32 mg) as a yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 9.17 (1H, s), 8.69 (1H, s), 7.46 (2H, d,J=7.8 Hz), 7.38-7.34 (1H, m), 5.88 (2H, s), 2.57 (3H, s).

ESI-MS found: 360 [M+K+2H]⁺

Example 158 Synthesis of1-(2,3-dichlorobenzyl)-3-methyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine[158] (hereinafter referred to as a compound [158])

The titled compound (20 mg) as a white solid was prepared from thecompound [153-2] obtained in the process (2) of Example 153 (103 mg) and2,3-dichlorobenzyl chloride (100 μL) according to the methods of theprocesses (3) and (4) of Example 153 and the process (2) of Example 134.

¹H-NMR (400 MHz, CD₃OD) δ: 9.19 (1H, d, J=1.5 Hz), 8.64 (1H, d, J=1.5Hz), 7.50 (1H, d, J=8.3 Hz), 7.25-7.21 (1H, m), 6.88 (1H, d, J=7.6 Hz),6.82 (2H, s) 2.66 (3H, s).

ESI-MS found: 360 [M+H]⁺

Example 159 Synthesis of potassium5-[1-(2,3-dichlorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-yl]-1H-tetrazole-1-ide[159] (hereinafter referred to as a compound [159])

To a solution of the compound [158] (20 mg) in ethanol (1.0 mL) wasadded an aqueous solution of 1N-potassium hydroxide (63 μL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (24 mg) as a yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 9.25 (1H, d, J=1.5 Hz), 8.55 (1H, d, J=1.5Hz), 7.48 (1H, d, J=8.1 Hz), 7.23-7.19 (1H, m), 6.81 (1H, d, J=7.6 Hz),5.80 (2H, s) 2.65 (3H, s).

ESI-MS found: 360 [M+K+2H]⁺

Example 160 Synthesis of1-(2-chloro-6-methylbenzyl)-3-methyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine[160] (hereinafter referred to as a compound [160])

The titled compound (44.5 mg) as a white solid was prepared from thecompound [153-2] obtained in the process (2) of Example 153 (111.4 mg)and 2-chloro-6-methylbenzyl chloride (138.0 mg) according to the methodsof the process (1) of Example 66, the process (4) of Example 153 and theprocess (2) of Example 134.

¹H-NMR (400 MHz, CD₃OD) δ: 9.12 (1H, d, J=1.5 Hz), 8.69 (1H, d, J=1.5Hz), 7.31 (1H, d, J=7.2 Hz), 7.28-7.25 (2H, m), 5.79 (2H, s), 2.59 (3H,s), 2.49 (3H, s).

ESI-MS found: 340 [M+H]⁺

Example 161 Synthesis of potassium5-[1-(2-chloro-6-methylbenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-yl]-1H-tetrazole-1-ide[161] (hereinafter referred to as a compound [161])

To a solution of the compound [160] (44.5 mg) in ethanol (4.5 mL) wasadded an aqueous solution of 1N-potassium hydroxide (133 μL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (46.0 mg) as a white solid.

¹H-NMR (400 MHz, CDCl3) δ: 9.15 (1H, d, J=1.2 Hz), 8.64 (1H, s), 7.30(1H, d, J=7.1 Hz), 7.27-7.22 (2H, m), 5.76 (2H, s), 2.58 (3H, s), 2.48(3H, s).

ESI-MS found: 340 [M+K−2H]⁺

Example 162 Synthesis of3-methyl-1-(naphthalene-1-yl)methyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine[162] (hereinafter referred to as a compound [162])

The titled compound (44 mg) as a white solid was prepared from thecompound [153-2] obtained in the process (2) of Example 153 (80 mg) and1-(chloromethyl)naphthalene (104 mg) according to the methods of theprocess (1) of Example 66, the process (4) of Example 153 and theprocess (2) of Example 134.

¹H-NMR (400 MHz, CD₃OD) δ: 9.20 (1H, d, J=1.2 Hz), 8.52 (1H, d, J=1.2Hz), 8.25 (1H, d, J=8.3 Hz), 7.90 (1H, d, J=6.8 Hz), 7.84 (1H, d, J=8.3Hz), 7.56-7.51 (2H, m), 7.43-7.39 (1H, m), 7.16 (1H, d, J=6.8 Hz), 6.16(2H, s), 2.67 (3H, s).

Example 163 Synthesis of1-(2,5-dimethylbenzyl)-3-methyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine[163] (hereinafter referred to as a compound [163])

The titled compound (57 mg) as a white solid was prepared from thecompound [153-2] obtained in the process (2) of Example 153 (102 mg) and2,5-dimethylbenzyl chloride (112 mg) according to the methods of theprocess (1) of Example 66, the process (4) of Example 153 and theprocess (2) of Example 134.

¹H-NMR (400 MHz, CD₃OD) δ: 9.17 (1H, d, J=1.7 Hz), 8.48 (1H, d, J=1.5Hz), 7.07 (1H, d, J=7.8 Hz), 7.00 (1H, d, J=7.3 Hz), 6.72 (1H, s), 5.62(2H, s), 2.65 (3H, s), 2.31 (3H, s), 2.19 (3H, s).

Example 164 Synthesis of1-(2-chloro-6-cyclopropylbenzyl)-3-methyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine[164] (hereinafter referred to as a compound [164])

The compound [156] obtained in Example 156 (30 mg), cyclopropylboronicacid (15 mg), tetrakis(triphenylphosphine)palladium(0) (5 mg) andpotassium carbonate (35 mg) were suspended in a mixed solvent (1.2 mL)of 1,4-dioxane/water (volume ratio 2/1), and the reaction mixture wassubjected to microwave irradiation at 160° C. for 1 hour. After coolingto room temperature, to the reaction mixture was added 3N-hydrochloricacid, and extracted with ethyl acetate. The obtained organic layer waswashed with water and brine successively, dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by reverse phase preparativeliquid chromatography to give the titled compound (13 mg) as a whitesolid.

1H-NMR (400 MHz, CD₃OD) δ: 9.12 (1H, d, J=1.5 Hz), 8.68 (1H, d, J=1.5Hz), 7.27-7.26 (2H, m), 7.13 (1H, d, J=6.8 Hz), 6.00 (2H, s), 2.59 (3H,s), 2.24-2.17 (1H, m), 0.92-0.89 (2H, m), 0.70-0.68 (2H, m).

ESI-MS found: 366 [M+H]⁺

Example 165 Synthesis of potassium5-[1-(2-chloro-6-cyclopropylbenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-yl]-1H-tetrazole-1-ide[165] (hereinafter referred to as a compound [165])

To a solution of the compound [164] (22 mg) in ethanol (2.0 mL) wasadded an aqueous solution of 1N-potassium hydroxide (60 μL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (20 mg) as a pale yellow solid.

1H-NMR (400 MHz, CD3OD) δ: 9.19 (1H, d, J=1.5 Hz), 8.60 (1H, d, J=1.5Hz), 7.32-7.25 (2H, m), 7.12 (1H, d, J=7.3 Hz), 5.96 (2H, s), 2.57 (3H,s), 2.18-2.16 (1H, m), 0.90-0.86 (2H, m), 0.68-0.66 (2H, m).

ESI-MS found: 366 [M+K+2H]⁺

Example 166 Synthesis of1-(2,6-dicyclopropylbenzyl)-3-methyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine[166] (hereinafter referred to as a compound [166])

The compound [156] obtained in Example 156 (47 mg), cyclopropylboronicacid (33 mg), tetrakis(triphenylphosphine)palladium(0) (8 mg) andpotassium carbonate (54 mg) were suspended in a mixed solvent (2.0 mL)of 1,4-dioxane/water (volume ratio 2/1), and the reaction mixture wassubjected to microwave irradiation at 160° C. for 1 hour. After coolingto room temperature, to the reaction mixture was added 3N-hydrochloricacid, and extracted with ethyl acetate. The obtained organic layer waswashed with water and brine successively, dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by reverse phase preparativeliquid chromatography to give the titled compound (17 mg) as a whitesolid.

¹H-NMR (400 MHz, CDCl₃) δ: 9.55 (1H, s), 8.48 (1H, s), 7.05 (2H, d,J=7.3 Hz), 6.18 (2H, s), 2.78 (3H, s), 1.91-1.87 (2H, m), 0.90-0.86 (4H,m), 0.69-0.66 (4H, m).

ESI-MS found: 372 [M+H]⁺

Example 167 Synthesis of1-(2,6-dichlorobenzyl)-3-ethyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylicacid [167] (hereinafter referred to as a compound [167])

(1) Synthesis of 6-bromo-3-ethyl-1H-pyrazolo[4,3-b]pyridine [167-1](hereinafter referred to as a compound [167-1])

The titled compound (225 mg) as a white solid was prepared from5-bromo-3-fluoropyridin-2-carbonitrile (201 mg) obtained by the methoddescribed in the document (Journal of Organic Chemistry, 2009, Vol. 74,p. 4547) and ethylmagnesium chloride according to the methods of theprocesses (1) and (2) of Example 153.

¹H-NMR (400 MHz, CDCl₃) δ: 9.87 (1H, s), 8.58 (1H, d, J=1.7 Hz), 7.95(1H, d, J=1.7 Hz), 3.12 (2H, q, J=7.6 Hz), 1.45 (3H, t, J=7.6 Hz).

(2) Synthesis of6-bromo-1-(2,6-dichlorobenzyl)-3-ethyl-1H-pyrazolo[4,3-b]pyridine[167-2] (hereinafter referred to as a compound [167-2])

The titled compound (325 mg) as a white solid was prepared from thecompound [167-1] obtained in the process (1) (223 mg) and2,6-dichlorobenzyl chloride (279 mg) according to the method of theprocess (1) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 8.51 (1H, d, J=1.7 Hz), 7.77 (1H, d, J=1.7Hz), 7.40 (2H, d, J=8.1 Hz), 7.29-7.27 (1H, m), 5.71 (2H, s), 3.04 (2H,q, J=7.6 Hz), 1.39 (3H, t, J=7.6 Hz).

(3) Synthesis of ethyl1-(2,6-dichlorobenzyl)-3-ethyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate[167-3] (hereinafter referred to as a compound [167-3])

To a solution of the compound [167-2] obtained in the process (2) (101mg) in ethanol (5 mL) were added triethylamine (0.2 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33 mg) atroom temperature, and then the reaction mixture was flushed with carbonmonoxide and heated at reflux for 18 hours. The reaction mixture wasquenched with water, and extracted with ethyl acetate. The obtainedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titledcompound (62 mg) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 9.11 (1H, s), 8.32 (1H, s), 7.40 (2H, d,J=8.1 Hz), 7.30-7.26 (1H, m), 5.81 (2H, s), 4.44 (2H, q, J=7.2 Hz), 3.10(2H, q, J=7.6 Hz), 1.44-1.40 (6H, m).

(4) Synthesis of1-(2,6-dichlorobenzyl)-3-ethyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylicacid [167]

The titled compound (40 mg) as a white solid was prepared from thecompound [167-3] obtained in the process (3) (62 mg) according to themethod of the process (2) of Example 117.

¹H-NMR (400 MHz, CD₃OD) δ: 9.04 (1H, d, J=1.5 Hz), 8.64 (1H, d, J=1.5Hz), 7.47 (2H, d, J=7.8 Hz), 7.38-7.36 (1H, m), 5.89 (2H, s), 3.03 (2H,q, J=7.5 Hz), 1.34 (3H, t, J=7.6 Hz).

Example 168 Synthesis of1-(2,6-dimethylbenzyl)-3-ethyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylicacid [168] (hereinafter referred to as a compound [168])

The titled compound (33 mg) as a white solid was prepared from thecompound [167-1] obtained in the process (1) of Example 167 (81 mg) and2,6-dimethylbenzyl chloride according to the methods of the process (1)of Example 66 and the processes (4) and (5) of Example 153.

¹H-NMR (400 MHz, CD₃OD) δ: 8.99 (1H, d, J=1.5 Hz), 8.20 (1H, d, J=1.5Hz), 7.20-7.16 (1H, m), 7.09 (2H, d, J=7.3 Hz), 5.67 (2H, s), 3.05 (2H,q, J=7.6 Hz), 2.31 (6H, s), 1.37 (3H, t, J=7.6 Hz).

ESI-MS found: 310 [M+H]⁺

Example 169 Synthesis of1-(2,3-dichlorobenzyl)-3-ethyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylicacid [169] (hereinafter referred to as a compound [169])

The titled compound (74 mg) as a white solid was prepared from thecompound [167-1] obtained in the process (1) of Example 167 (120 mg) and2,3-dichlorobenzyl chloride according to the methods of the process (1)of Example 66, and the processes (4) and (5) of Example 153.

¹H-NMR (400 MHz, CD₃OD) δ: 9.06 (1H, d, J=1.5 Hz), 8.58 (1H, d, J=1.5Hz), 7.48 (1H, d, J=7.8 Hz), 7.22-7.18 (1H, m), 6.84 (1H, d, J=7.3 Hz),5.79 (2H, s), 3.09 (2H, q, J=7.6 Hz), 1.40 (3H, t, J=7.6 Hz).

ESI-MS found: 350 [M+H]⁺

Example 170 Synthesis of1-(2-chloro-6-methylbenzyl)-3-ethyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylicacid [170] (hereinafter referred to as a compound [170])

The titled compound (1.1 mg) as a white solid was prepared from thecompound [167-1] obtained in the process (1) of Example 167 (144.1 mg)and 2-chloro-6-methylbenzyl chloride (167.4 mg) according to the methodsof the process (1) of Example 66, and the processes (4) and (5) ofExample 153.

¹H-NMR (400 MHz, CDCl3) δ: 9.02 (1H, d, J=1.2 Hz), 8.54 (1H, d, J=1.5Hz), 7.32 (1H, d, J=7.3 Hz), 7.28-7.24 (1H, m), 7.22 (1H, d, J=6.8 Hz),5.79 (2H, s), 3.04 (2H, q, J=7.6 Hz), 2.45 (3H, s), 1.36 (3H, t, J=7.6Hz).

ESI-MS found: 330 [M+H]⁺

Example 171 Synthesis of1-(2,6-dichlorobenzyl)-3-ethyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine[171] (hereinafter referred to as a compound [171])

The titled compound (40 mg) as a white solid was prepared from thecompound [167-1] obtained in the process (1) of Example 167 and2,6-dichlorobenzyl chloride according to the methods of the process (1)of Example 66, the process (4) of Example 153 and the process (2) ofExample 134.

¹H-NMR (400 MHz, CD₃OD) δ: 9.12 (1H, s), 8.72 (1H, d, J=1.5 Hz), 7.47(2H, d, J=7.8 Hz), 7.39-7.35 (1H, m), 5.90 (2H, s), 3.04 (2H, q, J=7.6Hz), 1.36 (3H, t, J=7.6 Hz).

ESI-MS found: 374 [M+H]⁺

Example 172 Synthesis of3-chloro-1-(2,6-dichlorobenzyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxylicacid [172] (hereinafter referred to as a compound [172])

(1) Synthesis of 5-bromo-3-fluoropyridine-2-carbaldehyde [172-1](hereinafter referred to as a compound [172-1])

5-Bromo-3-fluoropyridin-2-carbonitrile obtained by the method describedin the document (Journal of Organic Chemistry, 2009, Vol. 74, p. 4547)(4.5 g) was dissolved in dichloromethane (140 mL) and cooled to −78° C.1.0M toluene solution (33 mL) of diisobutylaluminum hydride was added at−78° C., and then the reaction mixture was warmed to 0° C. and stirredfor 5 minutes. The reaction mixture was cooled again to −78° C., andadded 3N-hydrochloric acid, and extracted with chloroform. The obtainedorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (848 mg) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 10.17 (1H, s), 8.69 (1H, s), 7.80 (1H, dd,J=9.1, 1.3 Hz).

(2) Synthesis of 6-bromo-1H-pyrazolo[4,3-b]pyridine [172-2] (hereinafterreferred to as a compound [172-2])

To a solution of the compound [172-1] obtained in the process (1) (426mg) in ethylene glycol (2.1 mL) was added hydrazine monohydrate (197 μL)at room temperature, and then the reaction mixture was stirred at 140°C. for 23 hours. After cooling to room temperature, to the reactionmixture was added water, and extracted with a mixed solution ofchloroform/isopropanol (volume ratio 10/1). The obtained organic layerwas washed with brine, dried over anhydrous sodium sulfate, filtered,and the filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography to give thetitled compound (275 mg) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 10.17 (1H, br), 8.65 (1H, d, J=1.7 Hz), 8.31(1H, s), 8.04 (1H, s).

ESI-MS found: 198 [M+H]⁺

(3) Synthesis of 6-bromo-3-chloro-1H-pyrazolo[4,3-b]pyridine [172-3](hereinafter referred to as a compound [172-3])

The compound [172-2] obtained in the process (2) (123 mg) inacetonitrile (4.1 mL) was added N-chlorosuccinimide (91 mg) at roomtemperature, and then the reaction mixture was stirred at 60° C. for 3hours. Furthermore, N-chlorosuccinimide (91 mg) was added at 60° C. andthe reaction mixture was stirred for 2 hours. After cooling to roomtemperature, to the reaction mixture was added an aqueous solution of1N-sodium hydroxide, and extracted with ethyl acetate. The obtainedorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure to give the titled compound (140 mg) as a pale yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 9.99 (1H, br), 8.69 (1H, d, J=2.0 Hz), 8.02(1H, d, J=2.0 Hz).

ESI-MS found: 232 [M+H]⁺

(4) Synthesis of6-bromo-3-chloro-1-(2,6-dichlorobenzyl)-1H-pyrazolo[4,3-b]pyridine[172-4] (hereinafter referred to as a compound [172-4])

The titled compound (171 mg) as a white solid was prepared from thecompound [172-3] obtained in the process (3) (140 mg) and2,6-dichlorobenzyl chloride according to the method of the process (1)of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 8.62 (1H, d, J=1.5 Hz), 7.93 (1H, d, J=1.5Hz), 7.41 (2H, d, J=8.1 Hz), 7.32-7.28 (1H, m), 5.72 (2H, s).

ESI-MS found: 390 [M+H]⁺

(5) Synthesis of3-chloro-1-(2,6-dichlorobenzyl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile[172-5] (hereinafter referred to as a compound [172-5])

The titled compound (64 mg) as a white solid was prepared from thecompound [172-4] obtained in the process (4) (100 mg) according to themethod of the process (4) of Example 153.

¹H-NMR (400 MHz, CDCl₃) δ: 8.79 (1H, d, J=1.5 Hz), 8.06 (1H, d, J=1.5Hz), 7.43 (2H, d, J=7.8 Hz), 7.36-7.32 (1H, m), 5.84 (2H, s).

ESI-MS found: 337 [M+H]⁺

(6) Synthesis of3-chloro-1-(2,6-dichlorobenzyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxylicacid [172]

The titled compound (33 mg) as a white solid was prepared from thecompound [172-5] obtained in the process (5) (36 mg) according to themethod of the process (5) of Example 153.

¹H-NMR (400 MHz, DMSO-d₆) δ: 9.08 (1H, s), 8.94 (1H, s), 7.57 (2H, d,J=8.1 Hz), 7.49-7.45 (1H, m), 5.95 (2H, s).

ESI-MS found: 356 [M+H]⁺

Example 173 Synthesis of potassium3-chloro-1-(2,6-dichlorobenzyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxylate[173] (hereinafter referred to as a compound [173])

To a solution of the compound [172] (27 mg) in ethanol (2.0 mL) wasadded an aqueous solution of 1N-potassium hydroxide (74 μL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (28 mg) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 9.06 (1H, s), 8.56 (1H, s), 7.56 (2H, d,J=8.1 Hz), 7.47-7.43 (1H, m), 5.82 (2H, s).

ESI-MS found: 356 [M+K+2H]⁺

Example 174 Synthesis of3-chloro-1-(2-chloro-6-methylbenzyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxylicacid [174] (hereinafter referred to as a compound [174])

(1) Synthesis of6-bromo-3-chloro-1-(2-chloro-6-methylbenzyl)-1H-pyrazolo[4,3-b]pyridine[174-1] (hereinafter referred to as a compound [174-1])

The titled compound (143 mg) as a white solid was prepared from thecompound [172-3] obtained in the process (3) of Example 172 (119 mg) and2-chloro-6-methylbenzyl chloride (107 mg) according to the method of theprocess (1) of Example 66.

¹H-NMR (400 MHz, CDCl₃) δ: 8.59 (1H, d, J=1.5 Hz), 7.82 (1H, d, J=1.5Hz), 7.32 (1H, d, J=8.1 Hz), 7.26-7.24 (1H, m), 7.18 (1H, d, J=7.3 Hz),5.64 (2H, s), 2.45 (3H, s).

ESI-MS found: 370 [M+H]⁺

(2) Synthesis of3-chloro-1-(2-chloro-6-methylbenzyl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile[174-2] (hereinafter referred to as a compound [174-2])

The titled compound (82 mg) as a white solid was prepared from thecompound [174-1] obtained in the process (1) (114 mg) according to themethod of the process (4) of Example 153.

¹H-NMR (400 MHz, CDCl₃) δ: 8.76 (1H, s), 7.95 (1H, s), 7.35-7.19 (3H,m), 5.74 (2H, s), 2.47 (3H, s).

ESI-MS found: 317 [M+H]⁺

(3) Synthesis of3-chloro-1-(2-chloro-6-methylbenzyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxylicacid [174]

The titled compound (35 mg) as a white solid was prepared from thecompound [174-2] obtained in the process (2) (38 mg) according to themethod of the process (5) of Example 153.

1H-NMR (400 MHz, DMSO-d₆) δ: 9.07 (1H, s), 8.93 (1H, s), 7.37-7.26 (3H,m), 5.84 (2H, s), 2.39 (3H, s).

ESI-MS found: 336 [M+H]⁺

Example 175 Synthesis of3-chloro-1-(2,6-dichlorobenzyl)-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine[175] (hereinafter referred to as a compound [175])

The titled compound (33 mg) as a white solid was prepared from thecompound [172-5] obtained in the process (5) of Example 172 (30 mg)according to the method of the process (2) of Example 134.

¹H-NMR (400 MHz, DMSO-d₆) δ: 9.24 (1H, s), 9.05 (1H, s), 7.58 (2H, d,J=8.1 Hz), 7.50-7.46 (1H, m), 5.94 (2H, s).

ESI-MS found: 380 [M+H]⁺

Example 176 Synthesis of potassium5-[3-chloro-1-(2,6-dichlorobenzyl)-1H-pyrazolo[4,3-b]pyridine-6-yl]-1H-tetrazole-1-ide[176] (hereinafter referred to as a compound [176])

To a solution of the compound [175] (17 mg) in ethanol (2.0 mL) wasadded an aqueous solution of 1N-potassium hydroxide (43 μL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (18 mg) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 9.27 (1H, s), 8.73 (1H, s), 7.57 (2H, d,J=8.1 Hz), 7.48-7.44 (1H, m), 5.88 (2H, s).

ESI-MS found: 380 [M+H]⁺

Example 177 Synthesis of3-chloro-1-(2-chloro-6-methylbenzyl)-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine[177] (hereinafter referred to as a compound [177])

The titled compound (41 mg) as a pale yellow solid was prepared from thecompound [174-2] obtained in the process (2) of Example 174 (42 mg)according to the method of the process (2) of Example 134.

1H-NMR (400 MHz, DMSO-d₆) δ: 9.22 (1H, s), 9.06 (1H, s), 7.38-7.28 (3H,m), 5.84 (2H, s), 2.44 (3H, s).

ESI-MS found: 360 [M+H]⁺

Example 178 Synthesis of potassium5-[3-chloro-1-(2-chloro-6-methylbenzyl)-1H-pyrazolo[4,3-b]pyridine-6-yl]-1H-tetrazole-1-ide[178] (hereinafter referred to as a compound [178])

To a solution of the compound [177] (30 mg) in ethanol (2.0 mL) wasadded an aqueous solution of 1N-potassium hydroxide (82 μL) at roomtemperature, and the solution was concentrated under reduced pressure togive the titled compound (33 mg) as a white solid.

1H-NMR (400 MHz, DMSO-d₆) δ: 9.26 (1H, s), 8.73 (1H, s), 7.38-7.26 (3H,m), 5.78 (2H, s), 2.41 (3H, s).

ESI-MS found: 360 [M+K+2H]⁺

Example 179 Synthesis of1-(2,6-dichlorobenzyl)-5-methoxy-3-methyl-1H-indazole-6-carboxylic acid[179] (hereinafter referred to as a compound [179])

(1) Synthesis of 4-bromo-2-fluoro-5-methoxybenzaldehyde [179-1](hereinafter referred to as a compound [179-1])

To a mixture of 2-bromo-4-fluoro-1-methoxybenzene (4.10 g) and titaniumtetrachloride (4.4 mL), dichloromethyl methyl ether (3.5 mL) was addedunder ice cooling, and then the reaction mixture was stirred at 0° C.for 2.5 hours. To the reaction mixture was added chloroform, and thereaction mixture was poured into ice water, and then stirred at roomtemperature for 1 hour. The organic layer was separated and dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The obtained residue was added hexane and theproduced solid was filtered to give the titled compound (1.61 g) as awhite solid.

¹H-NMR (400 MHz, CDCl₃) δ: 10.31 (1H, s), 7.46 (1H, d, J=9.0 Hz), 7.31(1H, d, J=5.9 Hz), 3.93 (3H, s).

(2) Synthesis of 1-(4-bromo-2-fluoro-5-methoxyphenyl)ethanone [179-2](hereinafter referred to as a compound [179-2])

The titled compound (382 mg) as a white solid was prepared from thecompound [179-1] obtained in the process (1) (1.61 g) andmethylmagnesium iodide according to the methods of the processes (1) and(2) of Example 140.

¹H-NMR (400 MHz, CDCl₃) δ: 7.40 (1H, d, J=9.8 Hz), 7.38 (1H, d, J=6.1Hz), 3.92 (3H, s), 2.64 (3H, d, J=5.4 Hz).

(3) Synthesis of6-bromo-1-(2,6-dichlorobenzyl)-5-methoxy-3-methyl-1H-indazole [179-3](hereinafter referred to as a compound [179-3])

To a solution of the compound [179-2] obtained in the process (2) (101mg) in dichloromethane (2 mL) was added titanium tetraisopropoxide (0.24mL) at room temperature, and then the reaction mixture was stirred atroom temperature for 15 minutes. Next, hydrazine monohydrate (0.04 mL)was added, and stirred at room temperature overnight. The reactionmixture was quenched with water and stirred for 3 hours, and then theinsoluble materials were filtered, and washed with ethyl acetate. Thefiltrate was dried over anhydrous sodium sulfate, filtered, concentratedunder reduced pressure to give a white solid. To the obtained solid wasadded 1,4-dioxane (2 mL) and water (1 mL). The reaction mixture wassubjected to microwave irradiation at 200° C. for 60 minutes, and thenthe reaction mixture was concentrated under reduced pressure. To asolution of the obtained residue in N,N-dimethylformamide (2 mL) wereadded potassium carbonate (127 mg) and 2,6-dichlorobenzyl chloride (117mg), and the reaction mixture was stirred at room temperature for 2days. The reaction mixture was quenched with water, and extracted withethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (43 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.61 (1H, s), 7.37 (2H, d, J=8.1 Hz),7.26-7.22 (1H, m), 6.97 (1H, s), 5.64 (2H, s), 3.93 (3H, s), 2.49 (3H,s).

ESI-MS found: 399 [M+H]⁺

(4) Synthesis of1-(2,6-dichlorobenzyl)-5-methoxy-3-methyl-1H-indazole-6-carbonitrile[179-4] (hereinafter referred to as a compound [179-4])

To a solution of the compound [179-3] obtained in the process (3) (39mg) in N,N-dimethylformamide (1.2 mL) were added zinc powder (7.2 mg),zinc cyanide (6.7 mg), tris(dibenzylideneacetone)palladium(0) (8.3 mg)and 1,1-bis(diphenylphosphino)ferrocene (5.8 mg). The reaction mixturewas stirred at 120° C. for 3 hours under argon atmosphere. To thereaction mixture was added 5% aqueous solution of potassium hydrogensulfate, and extracted with ethyl acetate. The obtained organic layerwas dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the titled compound (23 mg)as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.60 (1H, s), 7.39 (2H, d, J=8.1 Hz),7.29-7.25 (1H, m), 7.01 (1H, s), 5.71 (2H, s), 3.96 (3H, s), 2.51 (3H,s).

ESI-MS found: 346 [M+H]⁺

(5) Synthesis of1-(2,6-dichlorobenzyl)-5-methoxy-3-methyl-1H-indazole-6-carboxylic acid[179]

To a solution of the compound [179-4] (23 mg) obtained in the process(4) in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) was added anaqueous solution of 3N-sodium hydroxide (0.6 mL), and then the reactionmixture was subjected to microwave irradiation at 150° C. for 30minutes. To the reaction mixture was added 5% aqueous solution ofpotassium hydrogen sulfate, and extracted with ethyl acetate. Theobtained organic layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive the titled compound (13 mg) as a white solid.

¹H-NMR (400 MHz, CDCL₃) δ: 11.25 (1H, brs), 8.41 (1H, s), 7.38 (2H, d,J=7.8 Hz), 7.27-7.23 (1H, m), 7.14 (1H, s), 5.74 (2H, s), 4.13 (3H, s),2.52 (3H, s).

ESI-MS found: 365 [M+H]⁺

Example 180 Synthesis of1-(2,6-dichlorobenzyl)-5-hydroxy-3-methyl-1H-indazole-6-carboxylic acid[180] (hereinafter referred to as a compound [180])

To a suspension of the compound [179] (7.4 mg) in methylenechloride (0.2mL) was added 1M methylenechloride solution of borane tribromide (0.2mL) under ice-cooling, and then the reaction mixture was stirred at 0°C. for 3 hours. The reaction mixture was quenched with water, andextracted with ethyl acetate. The obtained organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by reversephase preparative liquid chromatography to give the titled compound (3.7mg) as a pale brown solid.

¹H-NMR (400 MHz, CD₃OD) δ: 8.17 (1H, s), 7.45 (1H, d, J=7.7 Hz), 7.45(1H, d, J=8.4 Hz), 7.34 (1H, dd, J=8.4, 7.7 Hz), 7.07 (1H, s), 5.73 (2H,s), 2.43 (3H, s).

ESI-MS found: 351 [M+H]⁺

Example 181 Synthesis of3-[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]-2-hydroxypropionicacid [181] (hereinafter referred to as a compound [181])

The titled compound (28 mg) as a white solid was prepared from thecompound [97-3] obtained in the process (3) of Example 97 (221 mg)according to the method of Example 128.

¹H-NMR (400 MHz, CD₃OD) δ: 7.52 (1H, d, J=7.6 Hz), 7.41-7.39 (3H, m),7.30 (1H, d, J=7.6 Hz), 7.09 (1H, d, J=8.1 Hz), 5.62 (2H, s), 4.32 (1H,s), 3.34-3.30 (1H, m), 3.01-2.98 (1H, m), 2.40 (3H, s).

Example 182 Synthesis of1-(2,6-dichlorobenzyl)-3-ethyl-6-(1H-tetrazole-5-yl)-1H-indazole [182](hereinafter referred to as a compound [182])

The titled compound (9 mg) as a white solid was prepared from thecompound [140-4] obtained in the process (4) of Example 140 (76 mg)according to the methods of the process (4) of Example 153 and theprocess (2) of Example 134.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.44 (1H, s), 7.98 (1H, d, J=8.3 Hz), 7.76(1H, d, J=8.3 Hz), 7.55 (2H, d, J=7.8 Hz), 7.46-7.42 (1H, m), 5.79 (2H,s) 2.88 (2H, q, J=7.6 Hz), 1.25 (3H, t, J=7.6 Hz).

ESI-MS found: 373 [M+H]⁺

Example 183 Synthesis of[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]difluoroacetic acid[183] (hereinafter referred to as a compound [183])

(1) Synthesis of ethyl[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]oxoacetate [183-1](hereinafter referred to as a compound [183-1])

To a solution of the compound [130-1] (1.47 g) obtained in the process(1) of Example 130 in tetrahydrofuran (15 mL) were addeddiisopropylethylamine (0.56 mL),tris(dibenzylideneacetone)dipalladium(0) (118 mg) and ethylchloroglyoxylate (0.42 mL) at 0° C., and then the reaction mixture wasstirred at room temperature for 24 hours. The reaction mixture wasquenched with water, and extracted with ethyl acetate. The obtainedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titledcompound (218 mg) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.10 (1H, s), 7.72 (2H, s), 7.38 (2H, d,J=8.1 Hz), 7.27-7.25 (1H, m), 5.81 (2H, s), 4.48 (2H, q, J=7.2 Hz), 2.56(3H, s), 1.45 (3H, t, J=7.1 Hz).

(2) Synthesis of ethyl[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]difluoroacetate[183-2] (hereinafter referred to as a compound [183-2])

To a solution of the compound [183-1] obtained in the process (1) (102mg) in dichloromethane (1 mL) was added N,N-diethylaminosulfurtrifluoride (0.35 mL), and then the reaction mixture was stirred at roomtemperature for 24 hours. The reaction mixture was quenched with waterand a saturated aqueous solution of sodium bicarbonate, and extractedwith chloroform. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the titled compound (100 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.70-7.68 (2H, m), 7.38 (2H, d, J=8.1 Hz),7.32 (1H, d, J=9.0 Hz), 7.25-7.23 (1H, m), 5.75 (2H, s), 4.29 (2H, q,J=7.2 Hz), 2.53 (3H, s), 1.29 (3H, t, J=7.1 Hz).

(3) Synthesis of[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]difluoroacetic acid[183]

To a solution of the compound [183-2] obtained in the process (2) (96mg) in ethanol (2 mL) was added an aqueous solution of 1N-sodiumhydroxide (2 mL) at room temperature, and then the reaction mixture wasstirred at 60° C. for 1 hour. The reaction mixture was added1N-hydrochloric acid, and the precipitated solid was filtered to givethe titled compound (89 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.81-7.79 (2H, m), 7.45 (2H, d, J=8.1 Hz),7.36-7.34 (2H, m), 5.81 (2H, s), 2.50 (3H, s).

ESI-MS found: 385 [M+H]⁺

Example 184 Synthesis of potassium[1-(2,6-dichlorobenzyl)-3-methyl-1H-indazole-6-yl]difluoroacetate [184](hereinafter referred to as a compound [184])

To a solution of the compound [183] (89 mg) in ethanol (2 mL) was addedan aqueous solution of 1N-potassium hydroxide (233 μL) at roomtemperature, and then the reaction mixture was stirred at roomtemperature for 10 minutes. The reaction mixture was concentrated underreduced pressure to give the titled compound (98 mg) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.88 (1H, s), 7.71 (1H, d, J=8.5 Hz),7.44-7.42 (3H, m), 7.35-7.33 (1H, m), 5.77 (2H, s), 2.48 (3H, s).

ESI-MS found: 385 [M+K+2H]⁺

Example 185 Synthesis of3-[1-(2-chloro-6-cyclopropylbenzyl)-3-methyl-1H-indazole-6-yl]propionicacid [185] (hereinafter referred to as a compound [185])

The titled compound (5.6 mg) as a white solid was prepared from thecompound [122-3] obtained in the process (3) of Example 122 (38 mg)according to the method of Example 164.

1H-NMR (400 MHz, CDCl₃) δ: 7.53 (1H, d, J=8.3 Hz), 7.29 (1H, d, J=8.1Hz) 7.21-7.17 (1H, m), 7.07 (1H, s), 6.97 (1H, d, J=7.6 Hz), 6.94 (1H,d, J=8.4 Hz), 5.83 (2H, s), 3.03 (2H, t, J=7.7 Hz), 2.68 (2H, t, J=7.6Hz), 2.51 (3H, s), 2.10-2.03 (1H, m), 0.87-0.82 (2H, m), 0.61-0.58 (2H,m).

ESI-MS found: 369 [M+H]⁺

Example 186 Synthesis of3-(2,6-dimethylbenzyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylicacid [186] (hereinafter referred to as a compound [186])

(1) Synthesis of methyl 3-nitro-4-(2,2,2-trifluoroacetylamino)benzoate[186-1] (hereinafter referred to as a compound [186-1])

To a solution of methyl 4-aminobenzoate (1.00 g) in trifluoroaceticanhydride (13 mL) was added potassium nitrate (0.74 g) under icecooling, and then the reaction mixture was stirred overnight. Thereaction mixture was quenched with ice water, and extracted with ethylacetate. The obtained organic layer was washed with a saturated aqueoussolution of sodium hydrogen carbonate and a saturated aqueous solutionof sodium chloride, and then dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive the titled compound (1.9 g) as a pale brown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 11.58 (1H, s), 8.99 (1H, d, J=2.0 Hz), 8.87(1H, d, J=8.8 Hz), 8.40 (1H, dd, J=8.8, 2.0 Hz), 4.00 (3H, s).

ESI-MS found: 291 [M−H]⁻

(2) Synthesis of methyl 4,4-di-tert-butoxycarbonylamino-3-nitrobenzoate[186-2] (hereinafter referred to as a compound [186-2])

To a solution of the compound [186-1] obtained in the process (1) (0.55g) in methanol (11 mL) was added 7% aqueous solution of potassiumcarbonate (5.5 mL), and then the reaction mixture was stirred at roomtemperature for 1.5 hours. The precipitated solid was filtered andwashed with water, and then eluted using chloroform-methanol. Thesolution was concentrated under reduced pressure. To the obtainedresidue were added a solution of di-tert-butyl dicarbonate (930 mg) intetrahydrofuran (15 mL), and triethylamine (0.31 mL), and then thereaction mixture was stirred at room temperature overnight. The reactionmixture was quenched with water, and extracted with ethyl acetate. Theobtained organic layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive the titled compound (0.68 g) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.71 (1H, d, J=2.0 Hz), 8.29 (1H, dd, J=8.1,2.0 Hz), 7.42 (1H, d, J=8.1 Hz), 3.99 (3H, s), 1.39 (18H, s).

ESI-MS found: 396 [M−H]⁻

(3) Synthesis of1-tert-butyl-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1,5-dicarboxylate[186-3] (hereinafter referred to as a compound [186-3])

To a solution of the compound [186-2]4 (118 mg) obtained in the process(2) in tetrahydrofuran (3 mL) was added 20% palladium hydroxide (66 mg),and the reaction mixture was stirred at room temperature for 1.5 hoursunder hydrogen atmosphere. The palladium on carbon was filtered, andthen the filtrate was concentrated under reduced pressure to give thetitled compound (43 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 10.28 (1H, brs), 7.87 (1H, dd, J=8.8, 2.0Hz), 7.84 (1H, d, J=2.0 Hz), 7.79 (1H, d, J=8.8 Hz), 3.93 (3H, s), 1.72(9H, s).

ESI-MS found: 291 [M−H]⁻

(4) Synthesis of methyl3-(2,6-dimethylbenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate[186-4] (hereinafter referred to as a compound [186-4])

To a solution of the compound [186-3] obtained in the process (3) (154mg) and 2,6-dimethylbenzyl chloride (163 mg) in N,N-dimethylformamide(2.6 mL) was added sodium hydride (31 mg), and then the reaction mixturewas stirred at room temperature for 4.5 hours. The reaction mixture wasquenched with water, and extracted with ethyl acetate. The obtainedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give a benzyl adduct(220 mg). To a solution of the obtained benzyl adduct (311 mg) inchloroform (7.6 mL) was added trifluoroacetic acid (7.6 mL), and thenthe reaction mixture was stirred at room temperature for 1.5 hours. Thereaction mixture was concentrated under reduced pressure, and then ethylacetate and hexane were added to the residue. The obtained solid wasfiltered, and dried under reduced pressure to give the titled compound(207 mg) as a white solid.

¹H-NMR (400 MHz, DMSO-d6) δ: 11.40 (1H, brs), 7.60 (1H, d, J=8.5 Hz),7.13 (1H, dd, J=8.1, 6.8 Hz), 7.10 (1H, s), 7.08-7.03 (3H, m), 5.05 (2H,s), 3.74 (3H, s), 2.29 (6H, s).

ESI-MS found: 309 [M−H]⁻

(5) Synthesis of methyl3-(2,6-dimethylbenzyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate[186-5] (hereinafter referred to as a compound [186-5])

To a solution of the compound [186-4] obtained in the process (4) (20mg) and 2-iodopropane (0.013 mL) in N,N-dimethylformamide (0.6 mL) wasadded sodium hydride (4 mg), and then the reaction mixture was stirredat room temperature overnight. To the reaction mixture was added 10 mLwater, and the reaction mixture was filled with InertSep K-solute(registered trademark). The reaction mixture was eluted with ethylacetate and the eluted liquid was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the titled compound (10 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.73 (1H, dd, J=8.3, 1.5 Hz), 7.18-7.04 (6H,m), 5.15 (2H, s), 4.77 (1H, septet, J=7.1 Hz), 3.82 (3H, s), 2.36 (6H,s), 1.56 (6H, d, J=7.1 Hz).

ESI-MS found: 353 [M+H]⁺

(6) Synthesis of3-(2,6-dimethylbenzyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylicacid [186]

To a solution of the compound [186-5] obtained in the process (5) (10mg) in tetrahydrofuran (2 mL) was added an aqueous solution of 1N-sodiumhydroxide (0.5 mL), and then the reaction mixture was subjected tomicrowave irradiation at 130° C. for 45 minutes. To the reaction mixturewas added 1M-hydrochloric acid, and the reaction mixture was extractedwith ethyl acetate. The obtained organic layer was concentrated underreduced pressure. The obtained residue was purified by reverse phasepreparative liquid chromatography to give the titled compound (3 mg) asa white solid.

ESI-MS found: 339 [M+H]⁺

Example 187 Test for uric acid transport inhibition using human URAT1expression cell

In this Example, it was evaluated whether the Example compound has theURAT1 inhibitory activity.

Human URAT1 full-length cDNA was introduced to an expression vectorpcDNA5/FRT/V5-His TOPO (registered trademark) (Invitrogen Corporation).The obtained expression plasmid was introduced to Chinese hamster ovarycell (hereinafter referred to as the CHO cell) by the liposome methodusing Lipofectamine LTX (Invitrogen), and cultured in a selection mediumincluding hygromycin, whereby to prepare human URAT1 stable expressioncell.

The human URAT1 expression CHO cell was cultured using D-MEM/F-12 (1:1)mixed medium including 10% bovine fetal serum and hygromycin at 37° C.in the presence of 5% CO₂. The cells were seeded onto a 96 well plate(Corning Incorporated) in 0.8×10⁵ cells/well, and after 24 hours, thetest for uric acid transport inhibition below was performed.

The medium was removed by aspiration, and then the cells were washedonce with an assay buffer including 125 mM of sodium gluconate, 4.8 mMof potassium gluconate, 1.2 mM of potassium dihydrogen phosphate, 1.2 mMof magnesium sulfate, 1.3 mM of calcium gluconate and 5.6 mM of glucose.50 μL assay buffer including the test compound in various concentrationswas added, and further 50 μL assay buffer including a radioactive ligand(uric acid labeled with ¹⁴C; 38 μM final concentration) was added, andincorporation reaction was performed at room temperature for 5 minutes.Immediately after completion of the reaction, the reaction mixture waswashed twice with 100 μL ice-cold assay buffer, and 100 μL of 0.1 Nsodium hydroxide was added. The reaction mixture was stirred to lyse thecells, and 4 mL Hionic-Fluor (Packard BioScience CO) was added, and thenthe radioactivity was measured with a liquid scintillation counter(Beckman Coulter, Inc. and Packard BioScience CO).

The radioactivity when each concentration of the test compound was added(uric acid incorporation activity, %) was calculated in which thedifference of the radioactivity when the test compound was not added(DMSO added), and the radioactivity when a positive control compound,benzbromarone (known URAT1 inhibitor) was added in 100 μM, was taken as100%, and the concentration of the test compound when the uric acidincorporation activity was inhibited to 50% (IC₅₀) was obtained. Theresults thereof are shown in Table 1.

TABLE 1 URAT1 Inhibitory Activity Test Compound (IC₅₀, nM) Compound ofExample 61 46 Compound of Example 64 22 Compound of Example 66 67Compound of Example 68 30 Compound of Example 75 77 Compound of Example78 24 Compound of Example 80 18 Compound of Example 82 15 Compound ofExample 84 53 Compound of Example 85 63 Compound of Example 86 28Compound of Example 87 88 Compound of Example 88 98 Compound of Example89 23 Compound of Example 91 43 Compound of Example 92 71 Compound ofExample 97 18 Compound of Example 99 41 Compound of Example 102 52Compound of Example 104 101 Compound of Example 106 55 Compound ofExample 107 77 Compound of Example 108 94 Compound of Example 109 335Compound of Example 111 75 Compound of Example 112 98 Compound ofExample 115 394 Compound of Example 117 91 Compound of Example 119 65Compound of Example 120 91 Compound of Example 121 41 Compound ofExample 122 10 Compound of Example 124 31 Compound of Example 125 72Compound of Example 128 576 Compound of Example 130 68 Compound ofExample 132 186 Compound of Example 133 16 Compound of Example 134 13Compound of Example 135 23 Compound of Example 136 34 Compound ofExample 137 10 Compound of Example 138 916 Compound of Example 139 653Compound of Example 140 24 Compound of Example 142 50 Compound ofExample 143 35 Compound of Example 144 42 Compound of Example 145 26Compound of Example 146 53 Compound of Example 147 76 Compound ofExample 148 49 Compound of Example 149 53 Compound of Example 150 295Compound of Example 152 184 Compound of Example 153 361 Compound ofExample 156 438 Compound of Example 158 292 Compound of Example 160 124Compound of Example 163 113 Compound of Example 164 55 Compound ofExample 167 80 Compound of Example 170 80 Compound of Example 171 52Compound of Example 172 162 Compound of Example 174 148 Compound ofExample 175 163 Compound of Example 177 104 Compound of Example 182 52Compound of Example 183 15 Compound of Example 185 17 Compound ofExample 186 165

From above, it was shown that the compound of the present inventionaccomplishes excellent URAT1 inhibitory action activity.

The correspondence relation of the compounds of Examples 1 to 186 withFormula (I) are shown below.

TABLE 2 (I)

R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— MethineMethine Methine Single Single COOH 1 Q¹: Methylene Bond R^(a): R^(b):Bond Bond A¹: Ph Hydrogen Hydrogen

Atom Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine MethineMethine Single Single COOH 2 Q¹: Methylene Bond R^(a): R^(b): Bond BondA¹: 2,6-Me₂Ph Hydrogen Hydrogen

Atom Atom

TABLE 3 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— MethineMethine Methine Single Single COOH 3 Q¹: Methylene Bond R^(a): R^(b):Bond Bond A¹: Hydrogen Hydrogen 2,4,6-Me₃Ph Atom Atom

Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine Methine MethineSingle (CR^(Yi)R^(Yi′))_(n) COOH 4 Q¹: Methylene Bond R^(a): R^(b): Bondn = 1 A¹: Ph Hydrogen Hydrogen —CH₂—

Atom Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine MethineMethine Single (CR^(Yi)R^(Yi′))_(n) COOH 5 Q¹: Methylene Bond R^(a):R^(b): Bond n = 1 A¹: 2,6-Me₂Ph Hydrogen Hydrogen —CH₂—

Atom Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine MethineMethine Single (CR^(Yi)R^(Yi′))_(n) COOH 6 Q¹: Methylene Bond R^(a):R^(b): Bond n = 1 A¹: 2-Me—Ph Hydrogen Hydrogen —CH₂—

Atom Atom

TABLE 4 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— MethineMethine Methine Single (CR^(Yi)R^(Yi′))_(n) COOH 7 Q¹: Methylene BondR^(a): R^(b): Bond n = 1 A¹: 2-Cl—Ph Hydrogen Hydrogen —CH₂—

Atom Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine MethineMethine Single (CR^(Yi)R^(Yi′))_(n) COOH 8 Q¹: Methylene Bond R^(a):R^(b): Bond n = 1 A¹: 2-CF₃—Ph Hydrogen Hydrogen —CH₂—

Atom Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine MethineMethine Single (CR^(Yi)R^(Yi′))_(n) COOH 9 Q¹: Methylene Bond R^(a):R^(b): Bond n = 1 A¹: 2-F—Ph Hydrogen Hydrogen —CH₂—

Atom Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine MethineMethine Single (CR^(Yi)R^(Yi′))_(n) COOH 10 Q¹: Methylene Bond R^(a):R^(b): Bond n = 1 A¹: 3-F—Ph Hydrogen Hydrogen —CH₂—

Atom Atom

TABLE 5 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— MethineMethine Methine Single (CR^(Yi)R^(Yi′))_(n) COOH 11 Q¹: Methylene BondR^(a): R^(b): Bond n = 1 A¹: 4-F—Ph Hydrogen Hydrogen —CH₂—

Atom Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine MethineMethine Single (CR^(Yi)R^(Yi′))_(n) COOH 12 Q¹: Methylene Bond R^(a):R^(b): Bond n = 1 A¹: Hydrogen Hydrogen —CH₂— 2-Cl-6-F—Ph Atom Atom

Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine Methine MethineSingle (CR^(Yi)R^(Yi′))_(n) COOH 13 Q¹: Methylene Bond R^(a): R^(b):Bond n = 1 A¹: Hydrogen Hydrogen —CH₂— 2-Cl-4-F—Ph Atom Atom

Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine Methine MethineSingle (CR^(Yi)R^(Yi′))_(n) COOH 14 Q¹: Methylene Bond R^(a): R^(b):Bond n = 1 A¹: Hydrogen Hydrogen —CH₂— 2-Cl-5-F—Ph Atom Atom

TABLE 6 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— MethineMethine Methine Single (CR^(Yi)R^(Yi′))_(n) COOH 15 Q¹: Methylene BondR^(a): R^(b): Bond n = 1 A¹: 3-Cl—Ph Hydrogen Hydrogen —CH₂—

Atom Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine MethineMethine Single (CR^(Yi)R^(Yi′))_(n) COOH 16 Q¹: Methylene Bond R^(a):R^(b): Bond n = 1 A¹: 4-Cl—Ph Hydrogen Hydrogen —CH₂—

Atom Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine MethineMethine Single (CR^(Yi)R^(Yi′))_(n) COOH 17 Q¹: Methylene Bond R^(a):R^(b): Bond n = 1 A¹: 2,6-Cl₂Ph Hydrogen Hydrogen —CH₂—

Atom Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine MethineMethine Single (CR^(Yi)R^(Yi′))_(n) COOH 18 Q¹: Methylene Bond R^(a):R^(b): Bond n = 1 A¹: 2,3-Cl₂Ph Hydrogen Hydrogen —CH₂—

Atom Atom

TABLE 7 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— MethineMethine Methine Single (CR^(Yi)R^(Yi′))_(n) COOH 19 Q¹: Methylene BondR^(a): R^(b): Bond n = 1 A¹: Hydrogen Hydrogen —CH₂—6-Cl-benzodioxole-5-yl Atom Atom

Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine Methine MethineSingle (CR^(Yi)R^(Yi′))_(n) COOH 20 Q¹: Methylene Bond R^(a): R^(b):Bond n = 1 A¹: 2,4-Cl₂Ph Hydrogen Hydrogen —CH₂—

Atom Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine MethineMethine Single (CR^(Yi)R^(Yi′))_(n) COOH 21 Q¹: Methylene Bond R^(a):R^(b): Bond n = 1 A¹: 2,5-Cl₂Ph Hydrogen Hydrogen —CH₂—

Atom Atom

TABLE 8 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Meth-Meth- Meth- Single (CR^(Yi)R^(Yi′))_(n) COOH 22 Q¹: Methylene bondR^(a): R^(b): ine ine ine Bond n = 1 A¹: Hydrogen Hydrogen —CH₂—2-F-6-CF₃Ph Atom Atom

Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Meth- Meth- Meth- Single(CR^(Yi)R^(Yi′))_(n) COOH 23 Q¹: Methylene bond R^(a): R^(b): ine ineine Bond n = 1 A¹: Hydrogen Hydrogen —CH₂— 4-F-2-CF₃Ph Atom Atom

Example 24 —Q¹—A¹ Q¹: Methylene A¹: 4-EtPh  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example 25 —Q¹—A¹ Q¹: Methylene A¹: 2,4-F₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH

TABLE 9 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 26 —Q¹—A¹ Q¹: Methylene A¹: 2,6-F₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example 27 —Q¹—A¹ Q¹: Methylene A¹: 2,5-F₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example 28 —Q¹—A¹ Q¹: Methylene A¹: 2,3-F₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example 29 —Q¹—A¹ Q¹: Methylene A¹: 3-CF₃Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH

TABLE 10 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 30 —Q¹—A¹ Q¹: Methylene A¹: 4-CF₃Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example 31 —Q¹—A¹ Q¹: Methylene A¹: 2,4-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example 32 —Q¹—A¹ Q¹: Methylene A¹: 2,5-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example 33 —Q¹—A¹ Q¹: Methylene A¹: 3-MePh  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH

TABLE 11 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 34 —Q¹—A¹ Q¹: Methylene A¹: 4-MePh  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example 35 —Q¹—A¹ Q¹: Methylene A¹: 4-pyridyl  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example 36 —Q¹—A¹ Q¹: Methylene A¹: 2-MeO—Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example 37 —Q¹—A¹ Q¹: Methylene A¹: 3-MeO—Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH

TABLE 12 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 38 —Q¹—A¹ Q¹: Methylene A¹: 4-MeO—Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Meth- Meth-Meth- Single (CR^(Yi)R^(Yi′))_(n) COOH 39 Q¹: Methylene bond R^(a):R^(b): ine ine ine Bond n = 1 A¹: Hydrogen Hydrogen —CH₂— 1-naphthyl-PhAtom Atom

Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Meth- Meth- Meth- Single(CR^(Yi)R^(Yi′))_(n) COOH 40 Q¹: Methylene bond R^(a): R^(b): ine ineine Bond n = 1 A¹: Hydrogen Hydrogen —CH₂— 2-naphthyl-Ph Atom Atom

Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Meth- Meth- Meth- Single(CR^(Yi)R^(Yi′))_(n) COOH 41 Q¹: Methylene bond R^(a): R^(b): ine ineine Bond n = 1 A¹: Hydrogen Hydrogen —CH₂— 6-Cl-pyridine Atom Atom

TABLE 13 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Meth-Meth- Meth- Single (CR^(Yi)R^(Yi′))_(n) COOH 42 Q¹: Methylene bondR^(a): R^(b): ine ine ine Bond n = 1 A¹: Hydrogen Hydrogen —CH₂—6-Me-pyridine- Atom Atom 2-yl

Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Meth- Meth- Meth- Single(CR^(Yi)R^(Yi′))_(n) COOH 43 Q¹: Methylene bond R^(a): R^(b): ine ineine Bond n = 1 A¹: Hydrogen Hydrogen —CH₂— biphenyl-2-yl Atom Atom

Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Meth- Meth- Meth- Single(CR^(Yi)R^(Yi′))_(n) COOH 44 Q¹: Methylene bond R^(a): R^(b): ine ineine Bond n = 1 A¹: Hydrogen Hydrogen —CH₂— biphenyl-3-yl Atom Atom

Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Meth- Meth- Meth- Single(CR^(Yi)R^(Yi′))_(n) COOH 45 Q¹: Methylene bond R^(a): R^(b): ine ineine Bond n = 1 A¹: Hydrogen Hydrogen —CH₂— biphenyl-4-yl Atom Atom

TABLE 14 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 46 —Q¹—A¹ Q¹: Methylene A¹: 3-PhO—Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example 47 —Q¹—A¹ Q¹: —(CH₂)₃— A¹: Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example 48 Lower alkyl group (isopropyl)  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example 49 Lower alkyl group (isobutyl)  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =1 —CH₂— COOH Example Lower alkyl Double ═C(R^(a))— ═C(R^(b))— Meth-Meth- Meth- Single (CR^(Yi)R^(Yi′))_(n) COOH 50 group that may bondR^(a): R^(b): ine ine ine Bond n = 1 be substituted Hydrogen Hydrogen—CH₂— with a Atom Atom cycloalkyl group (cyclohexyl- methyl)

TABLE 15 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 51 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═N— Meth- ine Meth- ineMeth- ine Single Bond Single Bond COOH Example 52 —Q¹—A¹ Q¹: MethyleneA¹: 2,6-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═N— Meth- ine Meth- ineMeth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂— COOH Example 53—Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph  

Double bond ═N— ═C(R^(b))— R^(b): Hydrogen Atom Meth- ine Meth- ineMeth- ine Single Bond Single Bond COOH

TABLE 16 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 54 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph  

Double bond ═N— ═C(R^(b))— R^(b): Hydrogen Atom Meth- ine Meth- ineMeth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂— COOH Example 55—Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Lower alkenylene —CH₂═CH₂— SingleBond COOH Example 56 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =2 —(CH₂)₂— COOH

TABLE 17 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 57 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =2 —CH(OH)CH₂— R^(Yi) = OH COOH Example 58 —Q¹—A¹ Q¹: Methylene A¹:2,6-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =5 —(CH₂)₅— COOH

TABLE 18 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 59 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine carbonyl (CR^(Yi)R^(Yi′))_(n) n = 2—(CH₂)₂— COOH Example 60 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): HydrogenAtom Meth- ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n =3 —(CH₂)₃— COOH Example 61 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): Me Meth-ine Meth- ine Meth- ine Single Bond Single Bond COOH

TABLE 19 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 62 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): Me Meth-ine Meth- ine Meth- ine Single Bond Single Bond COO⁻K⁺ Example 63 —Q¹—A¹Q¹: Methylene A¹: 2,6-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): Me Meth-ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂— OHExample 64 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): Me Meth-ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂—COOH

TABLE 20 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 65 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph  

Double bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): Me Meth-ine Meth- ine Meth- ine Single Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂—COO⁻K⁺ Example —Q¹—A¹ Double ═N— ═C(R^(b))— Meth- Meth- Meth- Single(CR^(Yi)R^(Yi′))_(n) COOH 66 Q¹: Methylene bond R^(b): Me ine ine ineBond n = 1 A¹: 2,6-Me₂Ph —CH₂—

TABLE 21 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— MethineMethine Methine Single (CR^(Yi)R^(Yi′))_(n) COOH 67 Q¹: Methylene BondR^(a): R^(b): Cl Bond n = 1 A¹: Ph Hydrogen —CH₂—

Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine Methine MethineSingle (CR^(Yi)R^(Yi′))_(n) COOH 68 Q¹: Methylene Bond R^(a): R^(b): ClBond n = 1 A¹: 2,6-Me₂Ph Hydrogen —CH₂—

Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine Methine MethineSingle Single COOH 69 Q¹: Methylene Bond R^(a): Me R^(b): Bond Bond A¹:2,6-Me₂Ph Hydrogen

Atom

TABLE 22 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— MethineMethine Methine Single Single COOH 70 Q¹: Methylene Bond R^(a): MeR^(b): Bond Bond A¹: Ph Hydrogen

Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine Methine MethineSingle Single COOH 71 Q¹: Methylene Bond R^(a): Me R^(b): Bond Bond A¹:2-MePh Hydrogen

Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine Methine MethineSingle Single COOH 72 Q¹: Methylene Bond R^(a): Me R^(b): Bond Bond A¹:2-ClPh Hydrogen

Atom Example —Q¹—A¹ Double ═C(R^(a))— ═N— Methine Methine Methine SingleSingle COOH 73 Q¹: Methylene Bond R^(a): CF₃ Bond Bond A¹: 2,6-Me₂Ph

TABLE 23 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Single ═C(R^(aa))(R^(ab))—═C(R^(ba))(R^(bb))— Meth- Methine Methine Single (CR^(Yi)R^(Yi′))_(n)COO⁻K⁺ 74 Q¹: Methylene Bond R^(aa): H R^(ba): H ine Bond n = 1 A¹: PhR^(ab): H R^(bb): H —CH₂—

Example —Q¹—A¹ Single ═C(R^(aa))(R^(ab))— ═C(R^(ba))(R^(bb))— Meth-Methine Methine Single (CR^(Yi)R^(Yi′))_(n) COOH 75 Q¹: Methylene BondR^(aa): H R^(ba): H ine Bond n = 1 A¹: 2,6-Me₂Ph R^(ab): H R^(bb): H—CH₂—

Example —Q¹—A¹ Single ═C(R^(aa))(R^(ab))— ═C(R^(ba))(R^(bb))— Meth-Methine Methine Single (CR^(Yi)R^(Yi′))_(n) COO⁻K⁺ 76 Q¹: Methylene BondR^(aa): H R^(ba): H ine Bond n = 1 A¹: 2,6-Me₂Ph R^(ab): H R^(bb): H—CH₂—

Example —Q¹—A¹ Single ═C(R^(aa))(R^(ab))— ═C(R^(ba))(R^(bb))— Meth-═C(Cl)— Methine Single (CR^(Yi)R^(Yi′))_(n) COOH 77 Q¹: Methylene BondR^(aa): H R^(ba): H ine Bond n = 1 A¹: 2,6-Me₂Ph R^(ab): H R^(bb): H—CH₂—

TABLE 24 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Single ═C(R^(aa))(R^(ab))—═C(R^(ba))(R^(bb))— Meth- Meth- Meth- Single (CR^(Yi)R^(Yi′))_(n) COOH78 Q¹: Methylene Bond R^(aa): H R^(ba): Me ine ine ine Bond n = 1 A¹:2,6-Me₂Ph R^(ab): H R^(bb): H —CH₂—

Example —Q¹—A¹ Single ═C(R^(aa))(R^(ab))— ═C(R^(ba))(R^(bb))— Meth-Meth- Meth- Single (CR^(Yi)R^(Yi′))_(n) COOH 79 Q¹: Methylene BondR^(aa): H R^(ba): Me ine ine ine Bond n = 1 A¹: 2,6-Me₂Ph R^(ab): HR^(bb): H —CH₂—

Chiral compound Example —Q¹—A¹ Single ═C(R^(aa))(R^(ab))—═C(R^(ba))(R^(bb))— Meth- Meth- Meth- Single (CR^(Yi)R^(Yi′))_(n) COOH80 Q¹: Methylene Bond R^(aa): H R^(ba): Me ine ine ine Bond n = 1 A¹:2,6-Me₂Ph R^(ab): H R^(bb): Me —CH₂—

TABLE 25 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Single ═C(R^(aa))(R^(ab))—═C(R^(ba))(R^(bb))— Meth- Meth- Meth- Single Single COOH 81 Q¹:Methylene Bond R^(aa): H R^(ba): H ine ine ine Bond Bond A¹: 2,6-Me₂PhR^(ab): H R^(bb): H

Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Meth- Meth- Meth- Single(CR^(Yi)R^(Yi′))_(n) COOH 82 Q¹: Methylene Bond R^(a): R^(b): ine ineine Bond n = 1 A¹: 2,6-Cl₂Ph Hydrogen Methyl —CH₂—

Atom Group Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Meth- Meth- Meth-Single (CR^(Yi)R^(Yi′))_(n) COO⁻K⁺ 83 Q¹: Methylene Bond R^(a): R^(b):ine ine ine Bond n = 1 A¹: 2,6-Cl₂Ph Hydrogen Methyl —CH₂—

Atom Group

TABLE 26 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— MethineMethine Methine Single (CR^(Yi)R^(Yi′))_(n) COOH 84 Q¹: Methylene BondR^(a): R^(b): bond n = 1 A¹: 2,3-Cl₂Ph Hydrogen Methyl —CH₂—

Atom Group Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine MethineMethine Single (CR^(Yi)R^(Yi′))_(n) COOH 85 Q¹: Methylene Bond R^(a):R^(b): Bond n = 1 A¹: 2,5-Me₂Ph Hydrogen Methyl —CH₂—

Atom Group

TABLE 27 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— MethineMethine Methine Single (CR^(Yi)R^(Yi′))_(n) COOH 86 Q¹: Methylene BondR^(a): R^(b): Methyl Bond n = 1 A¹: Hydrogen Group —CH₂— 2-Cl-6-F—PhAtom

Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine Methine MethineSingle (CR^(Yi)R^(Yi′))_(n) COOH 87 Q¹: Methylene Bond R^(a): R^(b):Methyl bond n = 1 A¹: 2-Cl—Ph Hydrogen Group —CH₂—

Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine Methine MethineSingle (CR^(Yi)R^(Yi′))_(n) COOH 88 Q¹: Methylene Bond R^(a): R^(b):Methyl bond n = 1 A¹: Hydrogen Group —CH₂— 6-Cl-benzo[d] Atom[1,3]dioxiole-5-yl

Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine Methine MethineSingle (CR^(Yi)R^(Yi′))_(n) COOH 89 Q¹: Methylene Bond R^(a): R^(b):Methyl Bond n = 2 A¹: 2,6-Cl₂Ph Hydrogen Group —CH₂—CH₂—

Atom

TABLE 28 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— MethineMethine Methine Single Single COOH 90 Q¹: Methylene Bond R^(a): R^(b):Acetyl Bond Bond A¹: 2,6-Me₂Ph Hydrogen Group

Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine Methine MethineSingle Single COOH 91 Q¹: Methylene Bond R^(a): R^(b): Ethyl Bond BondA¹: 2,6-Me₂Ph Hydrogen Group

Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine Methine MethineSingle Single COOH 92 Q¹: Methylene Bond R^(a): R^(b): Bond Bond A¹:2,6-Me₂Ph Hydrogen Isopropyl

Atom Group Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine MethineMethine Single (CR^(Yi)R^(Yi′))_(n) COOH 93 Q¹: Methylene Bond R^(a):^(b): Bond n = 1 A¹: Hydrogen Hydrogen —CH₂— 5-Cl-thiophene-2-yl AtomAtom

TABLE 29 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 94 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph

Double Bond ═C(R^(a))— R^(a): Hydrogen Atom ═C(R^(b))— R^(b): ChlorineAtom Methine Methine Methine Single Bond Single Bond

Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— —N═ Methine Methine SingleSingle COOH 95 Q¹: Methylene Bond R^(a): R^(b): Bond Bond A¹: 2,6-Me₂PhHydrogen Hydrogen

Atom Atom Example —Q¹—A¹ Double ═C(R^(a))— ═C(R^(b))— Methine Methine—N═ Single Single COOH 96 Q¹: Methylene Bond R^(a): R^(b): Bond Bond A¹:2,6-Me₂Ph Hydrogen Hydrogen

Atom Atom

TABLE 30 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═N— ═C(R^(b))— Meth- Meth-Meth- Single (CR^(Yi)R^(Yi′))_(n) COOH 97 Q¹: Methylene Bond R^(b):Methyl ine ine ine Bond n = 1 A¹: 2,6-Cl₂Ph Group —CH₂—

Example —Q¹—A¹ Double ═N— ═C(R^(b))— Meth- Meth- Meth- Single(CR^(Yi)R^(Yi′))_(n) COO⁻K⁺ 98 Q¹: Methylene Bond R^(b): Methyl ine ineine Bond n = 1 A¹: 2,6-Cl₂Ph Group —CH₂—

Example —Q¹—A¹ Double ═N— ═C(R^(b))— Meth- Meth- Meth- Single(CR^(Yi)R^(Yi′))_(n) COOH 99 Q¹: Methylene Bond R^(b): Methyl ine ineine Bond n = 1 A¹: 2,3-Cl₂Ph Group —CH₂—

TABLE 31 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═N— ═C(R^(b))— Meth- Meth-Meth- Single (CR^(Yi)R^(Yi′))_(n) COO⁻K⁺ 100 Q¹: Methylene Bond R^(b):Methyl ine ine ine Bond n = 1 A¹: 2,3-Cl₂Ph Group —CH₂—

Example —Q¹—A¹ Double ═N— ═C(R^(b))— Meth- Meth- Meth- Single(CR^(Yi)R^(Yi′))_(n) COOH 101 Q¹: Methylene Bond R^(b): Methyl ine ineine Bond n = 1 A¹: 2,5-Me₂Ph Group —CH₂—

TABLE 32 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═N— ═C(R^(b))— MethineMethine Methine Single (CR^(Yi)R^(Yi′))_(n) COOH 102 Q¹: Methylene BondR^(b): Methyl Bond n = 1 A¹: Group —CH₂— 2-Cl-6-MePh

Example —Q¹—A¹ Double ═N— ═C(R^(b))— Methine Methine Methine Single(CR^(Yi)R^(Yi′))_(n) COO⁻K⁺ 103 Q¹: Methylene Bond R^(b): Methyl Bond n= 1 A¹: Group —CH₂— 2-Cl-6-MePh

Example —Q¹—A¹ Double ═N— ═C(R^(b))— Methine Methine Methine Single(CR^(Yi)R^(Yi′))_(n) COOH 104 Q¹: Methylene Bond R^(b): Methyl Bond n =1 A¹: Group —CH₂— 2-Cl-6-FPh

TABLE 33 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═N— ═C(R^(b))— MethineMethine Methine Single (CR^(Yi)R^(Yi′))_(n) COOH 105 Q¹: Methylene BondR^(b): Methyl Bond n = 1 A¹: Group —CH₂— 3,5-dimethylisoxazole-4-yl

Example —Q¹—A¹ Double ═N— ═C(R^(b))— Methine Methine Methine Single(CR^(Yi)R^(Yi′))_(n) COOH 106 Q¹: Methylene Bond R^(b): Methyl Bond n =1 A¹: 5-chloro- Group —CH₂— benzo[b]thiophene-3-yl

Example —Q¹—A¹ Double ═N— ═C(R^(b))— Methine Methine Methine Single(CR^(Yi)R^(Yi′))_(n) COOH 107 Q¹: Methylene Bond R^(b): Methyl Bond n =1 A¹: Group —CH₂— Naphthalene-1-yl

TABLE 34 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example —Q¹—A¹ Double ═N— ═C(R^(b))— MethineMethine Methine Single (CR^(Yi)R^(Yi′))_(n) COOH 108 Q¹: Methylene BondR^(b): Methyl Bond Bond n = 1 A¹: Group —CH₂— 2,4,6-Me₃Ph

Example —Q¹—A¹ Double ═N— ═C(R^(b))— Methine Methine Methine Single(CR^(Yi)R^(Yi′))_(n) COOH 109 Q¹: Methylene Bond R^(b): Methyl Bond n =1 A¹: Group —CH₂— 2-Cl-6-CNPh

Example —Q¹—A¹ Double ═N— ═C(R^(b))— Methine Methine Methine Single(CR^(Yi)R^(Yi′))_(n) COO⁻K⁺ 110 Q¹: Methylene Bond R^(b): Methyl Bond n= 1 A¹: Group —CH₂— 2-Cl-6-CNPh

TABLE 35 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 111 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1, R^(Y1) = H, R^(Y1′) = Me—CH(CH₃)— COOH Example 112 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1, R^(Y1) = Me, R^(Y1′) = Me—C(CH₃)₂— COOH Example 113 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1, R^(Y1) = H, R^(Y1′) = Et—CH(CH₂CH₃)— COOH

TABLE 36 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 114 —Q¹—A¹ Q¹: Ethylene A¹: Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂— COOH Example 115 —Q¹—A¹ Q¹:Methylene A¹: Quinoline-8-yl  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂— COOH

TABLE 37 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 116 —Q¹—A¹ Q¹: Methylene A¹: Quinoline-8-yl 

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂— COO⁻K⁺ Example 117 —Q¹—A¹Q¹: Methylene A¹: 2,6-Me₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond Single Bond COOH Example 118 —Q¹—A¹ Q¹: Methylene A¹:2,6-Me₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond Single Bond COO⁻K⁺ Example 119 —Q¹—A¹ Q¹: Methylene A¹:2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond Single Bond COOH

TABLE 38 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 120 —Q¹—A¹ Q¹: Methylene A¹: 2,3-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond Single Bond COOH Example 121 —Q¹—A¹ Q¹: Methylene A¹:2,6-Me₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 2 —CH₂—CH₂— COOH Example 122 —Q¹—A¹Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 2 —CH₂—CH₂— COOH Example 123 —Q¹—A¹Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 2 —CH₂—CH₂— COO⁻K⁺

TABLE 39 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 124 —Q¹—A¹ Q¹: Methylene A¹: 5-chlorobenzo[b]thiophene- 3-yl  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 2 —CH₂—CH₂— COOH Example 125 —Q¹—A¹Q¹: Methylene A¹: 2-Cl-6-CNPh  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 2 —CH₂—CH₂— COOH Example 126 —Q¹—A¹Q¹: Methylene A¹: 2-Cl-6-CNPh  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 2 —CH₂—CH₂— COO⁻K⁺

TABLE 40 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 127 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 2, R^(Y1) = H, R^(Y1′) = OH,R^(Y2), R^(Y2′) = H —CH(OH)CH₂— COOH Example 128 —Q¹—A¹ Q¹: MethyleneA¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1, R^(Y1) = H, R^(Y1′) = OH—CH(OH)— COOH Example 129 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1, R^(Y1) = H, R^(Y1′) = OH—CH(OH)— COO⁻K⁺

TABLE 41 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 130 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineCarbonyl Group (CR^(Yi)R^(Yi′))_(n) n = 2 —CH₂—CH₂— COOH Example 131—Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂— CONH₂ Example 132 —Q¹—A¹Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 2 —CH₂—CH₂— CONH₂

TABLE 42 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 133 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 3 —CH₂—CH₂—CH₂— COOH Example 134—Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂—

Example 135 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 2, —CH₂—CH₂—

TABLE 43 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 136 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂—

  2-oxo-1,3,4- oxadiazolyl group Example 137 —Q¹—A¹ Q¹: Methylene A¹:2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂—

  2-thioxo-1,3,4- oxadiazolyl group Example 138 —Q¹—A¹ Q¹: Methylene A¹:2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineOxygen Atom (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂— COOH

TABLE 44 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 139 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂— SO₃H Example 140 —Q¹—A¹ Q¹:Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Ethyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂— COOH Example 141 —Q¹—A¹ Q¹:Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Ethyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂— COO⁻K⁺

TABLE 45 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 142 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Ethyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂— COOH Example 143 —Q¹—A¹ Q¹:Methylene A¹: 2,6-Me₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Ethyl Group Methine Methine MethineSingle Bond Single Bond COOH Example 144 —Q¹—A¹ Q¹: Methylene A¹:2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Ethyl Group Methine Methine MethineSingle Bond Single Bond COOH

TABLE 46 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 145 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Ethyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 2 —CH₂—CH₂— COOH Example 146 —Q¹—A¹Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Ethyl Group Methine Methine MethineVinylene Group —CH═CH— Single Bond COOH Example 147 —Q¹—A¹ Q¹: MethyleneA¹: 2,6-Me₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Isopropyl Group Methine MethineMethine Single Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂— COOH

TABLE 47 R1

W¹ W² W³ W⁴ W⁵ X Y Z Example 148 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Cyclopropyl Group Methine MethineMethine Single Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂— COOH Example 149—Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Chlorine Atom Methine Methine MethineSingle Bond Single Bond COOH Example 150 —Q¹—A¹ Q¹: Methylene A¹:2,6-Cl₂Ph  

Double Bond ═N— ═C(R^(b))— R^(b): Cyano Group Methine Methine MethineSingle Bond Single Bond COOH

TABLE 48 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 151 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine —N═Single Bond Single Bond COOH Example 152 —Q¹—A¹ Q¹: Methylene A¹:2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine —N═Single Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CH₂—

Example 153 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group —N═ Methine MethineSingle Bond Single Bond COOH

TABLE 49 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 154 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine —N═Single Bond Single Bond COO⁻K⁺ Example 155 —Q¹—A¹ Q¹: Methylene A¹:2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine —N═Single Bond Single Bond COOH Example 156 —Q¹—A¹ Q¹: Methylene A¹:2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group —N═ Methine MethineSingle Bond Single Bond

TABLE 50 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 157 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group —N═ Methine MethineSingle Bond Single Bond

Example 158 —Q¹—A¹ Q¹: Methylene A¹: 2,3-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group —N═ Methine MethineSingle Bond Single Bond

Example 159 —Q¹—A¹ Q¹: Methylene A¹: 2,3-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group —N═ Methine MethineSingle Bond Single Bond

Example 160 —Q¹—A¹ Q¹: Methylene A¹: 2-Cl-6-MePh

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group —N═ Methine MethineSingle Bond Single Bond

TABLE 51 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 161 —Q¹—A¹ Q¹: Methylene A¹: 2-Cl-6-MePh

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group —N═ Methine MethineSingle Bond Single Bond

Example 162 —Q¹—A¹ Q¹: Methylene A¹: Naphthalene-1-yl

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group —N═ Methine MethineSingle Bond Single Bond

Example 163 —Q¹—A¹ Q¹: Methylene A¹: 2,5-Me₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group —N═ Methine MethineSingle Bond Single Bond

TABLE 52 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 164 —Q¹—A¹ Q¹: Methylene A¹: 2-Cl-6-cyclopropyl Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group —N═ Methine MethineSingle Bond Single Bond

Example 165 —Q¹—A¹ Q¹: Methylene A¹: 2-Cl-6-cyclo- propyl Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group —N═ Methine MethineSingle Bond Single Bond

Example 166 —Q¹—A¹ Q¹: Methylene A¹: 2,6-dicyclopropyl Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group —N═ Methine MethineSingle Bond Single Bond

TABLE 53 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 167 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Ethyl Group —N═ Methine Methine SingleBond Single Bond COOH Example 168 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Me₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Ethyl Group —N═ Methine Methine SingleBond Single Bond COOH Example 169 —Q¹—A¹ Q¹: Methylene A¹: 2,3-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Ethyl Group —N═ Methine Methine SingleBond Single Bond COOH

TABLE 54 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 170 —Q¹—A¹ Q¹: Methylene A¹: 2-Cl-6-MePh

Double Bond ═N— ═C(R^(b))— R^(b): Ethyl Group —N═ Methine Methine SingleBond Single Bond COOH Example 171 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Ethyl Group —N═ Methine Methine SingleBond Single Bond

Example 172 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Chlorine Atom —N═ Methine MethineSingle Bond Single Bond COOH

TABLE 55 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 173 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Chlorine Atom —N═ Methine MethineSingle Bond Single Bond COO⁻K⁺ Example 174 —Q¹—A¹ Q¹: Methylene A¹:2-Cl-6-MePh

Double Bond ═N— ═C(R^(b))— R^(b): Chlorine Atom —N═ Methine MethineSingle Bond Single Bond COOH Example 175 —Q¹—A¹ Q¹: Methylene A¹:2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Chlorine Atom —N═ Methine MethineSingle Bond Single Bond

TABLE 56 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 176 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Chlorine —N═ Methine Methine SingleBond Single Bond

Example 177 —Q¹—A¹ Q¹: Methylene A¹: 2-Cl-6-MePh

Double Bond ═N— ═C(R^(b))— R^(b): Chlorine Atom —N═ Methine MethineSingle Bond Single Bond

Example 178 —Q¹—A¹ Q¹: Methylene A¹: 2-Cl-6-MePh

Double Bond ═N— ═C(R^(b))— R^(b): Chlorine Atom —N═ Methine MethineSingle Bond Single Bond

TABLE 57 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 179 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine

Methine Single Bond Single Bond COOH Example 180 —Q¹—A¹ Q¹: MethyleneA¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine

Methine Single Bond Single Bond COOH Example 181 —Q¹—A¹ Q¹: MethyleneA¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 2 —CH2CH(OH)— R^(Y1), R^(Y1′),R^(Y2′)═H, R^(Y2)═OH COOH

TABLE 58 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 182 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond Single Bond

Example 183 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CF₂— R^(Y1)═R^(Y1′)═F COOHExample 184 —Q¹—A¹ Q¹: Methylene A¹: 2,6-Cl₂Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine MethineSingle Bond (CR^(Yi)R^(Yi′))_(n) n = 1 —CF₂— R^(Y1)═R^(Y1′)═F COO⁻K⁺

TABLE 59 R¹

W¹ W² W³ W⁴ W⁵ X Y Z Example 185 —Q¹—A¹ Q¹: Methylene A¹: 2-Cl-6-cycloproply Ph

Double Bond ═N— ═C(R^(b))— R^(b): Methyl Group Methine Methine —N═Single Bond (CR^(Yi)R^(Yi′))_(n) n = 2 —CH₂—CH₂— COOH Example 186 —Q¹—A¹Q¹: Methylene A¹: 2,6-Me₂Ph

Single Bond —(C═O)— ═N(R^(bc))— R^(bc): Isopropyl Group Methine Methine—N═ Single Bond Single Bond COOH

INDUSTRIAL APPLICABILITY

The compound represented by Formula (I) of the present invention and apharmaceutically acceptable salt and ester of the compound haveexcellent URAT1 inhibitory action, and thus can reduce the blood uricacid level, and are useful as an agent for treating or preventingpathological conditions associated with the blood uric acid such ashyperuricemia, gouty node, acute gout arthritis, chronic gout arthritis,gouty kidney, urolithiasis, a renal function disorder, a coronary arterydisease or an ischemic heart disease.

The invention claimed is:
 1. A compound represented by Formula (I):

[in the formula, R¹ represents a group represented by the generalformula: -Q¹-A¹; Q¹ represents a methylene group; A¹ represents a phenylgroup, which may be substituted with one to three substituents selectedfrom the <Substituent group L> described later (herein any twosubstituents adjacent to each other on the phenyl group may jointogether to form a lower alkylenedioxy group);

represents a double bond or a single bond; when

is a double bond, W¹ represents a nitrogen atom or a group representedby the general formula: ═C(R^(a))—, and W² represents a nitrogen atom ora group represented by the general formula: ═C(R^(b))—; when

is a single bond, W¹ represents a group represented by the generalformula: —C(R^(aa))(R^(ab))— or a group represented by the generalformula: —(C═O)—, and W² represents a group represented by the generalformula: —C(R^(ba))(R^(bb))—, a group represented by the generalformula: —(C═O)— or a group represented by the general formula:—N(R^(bc))—; R^(a) and R^(b) represent each independently a hydrogenatom, a substituent selected from the <Substituent group M> describedlater or a group represented by the general formula: -Q²-A²; R^(aa) andR^(ab) represent each independently a hydrogen atom, a substituentselected from the <Substituent group N> described later or a grouprepresented by the general formula: -Q²-A², or R^(aa) and R^(ab) mayjoin together to form a lower alkylene group (herein 1 to 2 or moremethylene groups constituting the lower alkylene group eachindependently may be substituted with an oxygen atom, a carbonyl group,a vinylene group or a group represented by the general formula:—N(R^(c))— for the total methylene groups, and/or the hydrogenconstituting the methylene group may be substituted with a hydroxylgroup, a lower alkyl group or a halogen atom); R^(ba) and R^(bb)represent each independently a hydrogen atom, a halogen atom, an aminogroup, a lower alkyl-amino group, a di-lower alkyl-amino group, ahydroxy-lower alkyl-amino group, a lower alkyl-sulfonylamino group, alower alkoxy-carbonylamino group, a substituent selected from the<Substituent group N> or a group represented by the general formula:-Q²-A², or R^(ba) and R^(bb) may join together to form a lower alkylenegroup (herein 1 to 2 or more methylene groups constituting the loweralkylene group each independently may be substituted with an oxygenatom, a carbonyl group, a vinylene group or a group represented by thegeneral formula: —N(R^(c))— for the total methylene groups, and/or thehydrogen constituting the methylene group may be substituted with ahydroxyl group, a lower alkyl group or a halogen atom); R^(bc)represents a group selected from the group consisting of a hydrogenatom, a lower alkyl group, a cycloalkyl group, a halo-lower alkyl group,a lower alkoxy-carbonyl group, a carbamoyl group, a mono-loweralkyl-carbamoyl group, a di-lower alkyl-carbamoyl group and a loweralkanoyl group or a group represented by the general formula: -Q²-A²; Q²represents a single bond, a lower alkylene group or a lower alkenylenegroup (herein 1 or 2, or more methylene groups constituting the loweralkylene group each independently may be substituted with an oxygenatom, a nitrogen atom or a carbonyl group for the total methylenegroups, and/or the hydrogen constituting the methylene group may besubstituted with a halogen atom, a cyano group, a hydroxyl group or alower alkyl group); A² represents a cycloalkyl group, an aliphaticheterocyclic group, an aryl group or a heteroaryl group, which may besubstituted with one to three substituents selected from the<Substituent group L> (herein any two substituents adjacent to eachother on the aryl group or the heteroaryl group may join together toform a lower alkylenedioxy group); W³ represents a nitrogen atom, and W⁴and W⁵ represent each independently a methine group that may have asubstituent selected from the group consisting of a halogen atom, ahydroxyl group, a cyano group, a lower alkyl group, a cycloalkyl group,a halo-lower alkyl group, a lower alkoxy group and a halo lower alkoxygroup; X represents a single bond; Y is a single bond; Z represents a5-tetrazolyl group, a 5-oxo-1,2,4-oxadiazolyl group, a2-oxo-1,3,4-oxadiazolyl group, a 5-imino-4,5-dihydro-1,3,4-oxadiazolylgroup, a 2-thioxo-1,3,4-oxadiazolyl group or a 5-oxo-1,2,4-thiadiazolylgroup; wherein, the <Substituent group L>, the <Substituent group M> andthe <Substituent group N> are defined as described below: <Substituentgroup L>: a halogen atom, a hydroxyl group, a nitro group, a cyanogroup, a formyl group, an amino group, a carboxyl group, a lower alkylgroup, a halo-lower alkyl group, a cycloalkyl group, a lower alkoxygroup, a halo-lower alkoxy group, a hydroxy lower alkyl group, a loweralkoxy lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoylgroup, a lower alkylthio group, a lower alkylsulfonyl group, a loweralkylamino group, a di-lower alkylamino group, a carbamoyl group, amono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, alower alkanoylamino group, a lower alkylsulfonylamino group, a loweralkoxycarbonylamino group, an aralkyl group, an aryloxy group, aheteroaryloxy group, and a lower alkenyl group, <Substituent group M>: ahalogen atom, a hydroxyl group, a nitro group, a cyano group, a formylgroup, an amino group, a carboxyl group, a lower alkyl group, ahalo-lower alkyl group, a cycloalkyl group, a lower alkoxy group, ahalo-lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxylower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group,a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylaminogroup, a di-lower alkylamino group, a carbamoyl group, a mono-loweralkyl carbamoyl group, a di-lower alkyl carbamoyl group, a loweralkanoylamino group, a lower alkylsulfonylamino group, and a loweralkoxycarbonylamino group, <Substituent group N>: a hydroxyl group, acyano group, a formyl group, a carboxyl group, a lower alkyl group, ahalo-lower alkyl group, a cycloalkyl group, a lower alkoxy group, ahalo-lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxylower alkyl group, lower alkoxycarbonyl group, a lower alkanoyl group, acarbamoyl group, a mono-lower alkyl carbamoyl group, and a di-loweralkyl carbamoyl group]; or a pharmaceutically acceptable salt or esterof the compound.
 2. The compound according to claim 1, wherein thesubstructure described below:

is selected from the following:

or a pharmaceutically acceptable salt or ester of the compound.
 3. Thecompound according to claim 1, wherein the <Substituent group L> is thegroup consisting of a hydroxyl group, a halogen atom, a cyano group, amethyl group, an ethyl group, a cyclopropyl group, a trifluoromethylgroup, a hydroxymethyl group, a methoxy group and a trifluoromethoxygroup, or a pharmaceutically acceptable salt or ester of the compound.4. A compound according to claim 1, or a pharmaceutically acceptablesalt or ester of the compound, wherein the compound is any one of thefollowing (n), (o) and (r): (n)1-(2-chloro-6-methylbenzyl)-3-methyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine,(o)1-(2-chloro-6-cyclopropylbenzyl)-3-methyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine,or (r)3-chloro-1-(2-chloro-6-methylbenzyl)-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine.5. The compound according to claim 1, which is1-(2-chloro-6-methylbenzyl)-3-methyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine,or a pharmaceutically acceptable salt of the compound.
 6. The compoundaccording to claim 1, which is1-(2-chloro-6-cyclopropylbenzyl)-3-methyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine,or a pharmaceutically acceptable salt of the compound.
 7. The compoundaccording to claim 1, which is3-chloro-1-(2-chloro-6-methylbenzyl)-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine,or a pharmaceutically acceptable salt of the compound.
 8. A URAT1inhibitor comprising the compound according to claim 1 or apharmaceutically acceptable salt or ester of the compound.
 9. An agentfor reducing uric acid level in blood, wherein the agent comprises thecompound according to claim 1 or a pharmaceutically acceptable salt orester of the compound.
 10. A compound represented by Formula (I-2):

[in the formula, R¹ represents a group represented by the generalformula: -Q¹-A¹; Q1 represents a methylene group; A¹ represents a phenylgroup, which may be substituted with one to three substituents selectedfrom the <Substituent group L> described later (herein any twosubstituents adjacent to each other on the phenyl group may jointogether to form a lower alkylenedioxy group);

represents a double bond or a single bond; when

is a double bond, W¹ represents a nitrogen atom or a group representedby the general formula: ═C(R^(a))—, and W² represents a nitrogen atom ora group represented by the general formula: ═C(R^(b))—; when

is a single bond, W¹ represents a group represented by the generalformula: —C(R^(aa))(R^(ab))— or a group represented by the generalformula: —(C═O)—, and W² represents a group represented by the generalformula: —C(R^(ba))(R^(bb))—, a group represented by the generalformula: —(C═O)— or a group represented by the general formula:—N(R^(bc))—; R^(a) and R^(b) represent each independently a hydrogenatom, a substituent selected from the <Substituent group M> describedlater or a group represented by the general formula: -Q₂-A₂; R^(aa) andR^(ab) represent each independently a hydrogen atom, a substituentselected from the <Substituent group N> described later or a grouprepresented by the general formula: -Q²-A², or R^(aa) and R^(ab) mayjoin together to form a lower alkylene group (herein 1 to 2 or moremethylene groups constituting the lower alkylene group eachindependently may be substituted with an oxygen atom, a carbonyl group,a vinylene group or a group represented by the general formula:—N(R^(c))— for the total methylene groups, and/or the hydrogenconstituting the methylene group may be substituted with a hydroxylgroup, a lower alkyl group or a halogen atom); R^(ba) and R^(bb)represent each independently a hydrogen atom, a halogen atom, an aminogroup, a lower alkyl-amino group, a di-lower alkyl-amino group, ahydroxy-lower alkyl-amino group, a lower alkyl-sulfonylamino group, alower alkoxy-carbonylamino group, a substituent selected from the<Substituent group N> or a group represented by the general formula:-Q²-A², or R^(ba) and R^(bb) may join together to form a lower alkylenegroup (herein 1 to 2 or more methylene groups constituting the loweralkylene group each independently may be substituted with an oxygenatom, a carbonyl group, a vinylene group or a group represented by thegeneral formula: —N(R^(c))— for the total methylene groups, and/or thehydrogen constituting the methylene group may be substituted with ahydroxyl group, a lower alkyl group or a halogen atom); R^(bc)represents a group selected from the group consisting of a hydrogenatom, a lower alkyl group, a cycloalkyl group, a halo-lower alkyl group,a lower alkoxy-carbonyl group, a carbamoyl group, a mono-loweralkyl-carbamoyl group, a di-lower alkyl-carbamoyl group and a loweralkanoyl group or a group represented by the general formula: -Q²-A²; Q²represents a single bond, a lower alkylene group or a lower alkenylenegroup (herein 1 or 2, or more methylene groups constituting the loweralkylene group each independently may be substituted with an oxygenatom, a nitrogen atom or a carbonyl group for the total methylenegroups, and/or the hydrogen constituting the methylene group may besubstituted with a halogen atom, a cyano group, a hydroxyl group or alower alkyl group); A² represents a cycloalkyl group, an aliphaticheterocyclic group, an aryl group or a heteroaryl group, which may besubstituted with one to three substituents selected from the<Substituent group L> (herein any two substituents adjacent to eachother on the aryl group or the heteroaryl group may join together toform a lower alkylenedioxy group); W⁴ and W⁵ represent a methine group;X represents a single bond; Y is a single bond; the <Substituent groupL>, the <Substituent group M> and the <Substituent group N> are definedas described below: <Substituent group L>: a halogen atom, a hydroxylgroup, a nitro group, a cyano group, a formyl group, an amino group, acarboxyl group, a lower alkyl group, a halo-lower alkyl group, acycloalkyl group, a lower alkoxy group, a halo-lower alkoxy group, ahydroxy lower alkyl group, a lower alkoxy lower alkyl group, a loweralkoxycarbonyl group, a lower alkanoyl group, a lower alkylthio group, alower alkylsulfonyl group, a lower alkylamino group, a di-loweralkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group,a di-lower alkyl carbamoyl group, a lower alkanoylamino group, a loweralkylsulfonylamino group, a lower alkoxycarbonylamino group, an aralkylgroup, an aryloxy group, a heteroaryloxy group, and a lower alkenylgroup, <Substituent group M>: a halogen atom, a hydroxyl group, a nitrogroup, a cyano group, a formyl group, an amino group, a carboxyl group,a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, alower alkoxy group, a halo-lower alkoxy group, a hydroxy lower alkylgroup, a lower alkoxy lower alkyl group, a lower alkoxycarbonyl group, alower alkanoyl group, a lower alkylthio group, a lower alkylsulfonylgroup, a lower alkylamino group, a di-lower alkylamino group, acarbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkylcarbamoyl group, a lower alkanoylamino group, a lower alkylsulfonylaminogroup, and a lower alkoxycarbonylamino group, <Substituent group N>: ahydroxyl group, a cyano group, a formyl group, a carboxyl group, a loweralkyl group, a halo-lower alkyl group, a cycloalkyl group, a loweralkoxy group, a halo-lower alkoxy group, a hydroxy lower alkyl group, alower alkoxy lower alkyl group, lower alkoxycarbonyl group, a loweralkanoyl group, a carbamoyl group, a mono-lower alkyl carbamoyl group,and a di-lower alkyl carbamoyl group]; or a pharmaceutically acceptablesalt or ester of the compound.
 11. The compound according to claim 10,which is1-(2,3-dichlorobenzyl)-3-methyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine,or a pharmaceutically acceptable salt of the compound.
 12. The compoundaccording to claim 10, which is1-(2,6-dichlorobenzyl)-3-ethyl-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine,or a pharmaceutically acceptable salt of the compound.
 13. The compoundaccording to claim 10, which is3-chloro-1-(2,6-dichlorobenzyl)-6-(1H-tetrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine,or a pharmaceutically acceptable salt of the compound.